6-hydroxy-4-oxo-1,4-dihydropyrimidine-5-carboxamides as apj agonists

ABSTRACT

The present invention provides compounds of Formula (I): 
     
       
         
         
             
             
         
       
     
     wherein all variables are as defined in the specification, and compositions comprising any of such novel compounds. These compounds are APJ agonists which may be used as medicaments.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority of U.S. Provisional Application Ser.No. 62/312,780, filed Mar. 24, 2016, which is incorporated herein in itsentirety.

FIELD OF THE INVENTION

The present invention provides novel1,4-dihydropyrimidine-5-carboxamides, and their analogues thereof, whichare APJ agonists, compositions containing them, and methods of usingthem, for example, for the treatment or prophylaxis of heart failure,atherosclerosis, ischemic heart disease and related conditions.

BACKGROUND OF THE INVENTION

Heart failure (HF) and related complications constitute major healthburden in developed countries with an estimated prevalence of 5,700,000in the United States alone (Roger, V. L. et al., Circulation,125(1):e2-e220 (2012)). Despite considerable advances in recent twodecades, the prognosis remains very poor, with survival rates of only˜50% within 5-years of diagnosis (Roger, V. L. et al., JAMA,292(3):344-350 (2004)). In addition to poor survival, the impairedquality of life and recurrent hospitalizations constitute clear unmetmedical need for development of novel treatment options.

HF is a clinical syndrome characterized by the inability of the heart todeliver sufficient supply of blood and oxygen to meet the metabolicdemands of organs in the body. Main symptoms associated with HF includeshortness of breath due to pulmonary edema, fatigue, reduced toleranceto exercise and lower extremity edemas. The etiology of HF is highlycomplex with multiple associated risk factors and potential causes.

Among the leading causes of HF are coronary artery disease and cardiacischemia, acute myocardial infarction, intrinsic cardiomyopathies andchronic uncontrolled hypertension. HF can develop either acutely(functional impairment post myocardial infarction) or as a chroniccondition, characterized by long-term maladaptive cardiac tissueremodeling, hypertrophy and cardiac dysfunction (for example due touncontrolled long-term hypertension). According to the diagnosticcriteria and type of ventricular dysfunction, HF is classified to twomajor groups, HF with “reduced ejection fraction” (HFrEF) or HF with“preserved ejection fraction” (HFpEF). Both types are associated withsimilar signs and symptoms, but differ in the type of ventricularfunctional impairment (Borlaug, B. A. et al., Eur. Heart J.,32(6):670-679 (2011)).

APJ receptor (APLNR) and its endogenous peptidic ligand apelin have beenimplicated as important modulators of cardiovascular function andcandidates for therapeutic intervention in HF (for review see Japp, A.G. et al., Biochem. Pharmacol., 75(10):1882-1892 (2008)).

Accumulated evidence from preclinical disease models and human heartfailure patients have implicated apelin and APJ agonism as beneficial inthe setting of HF. Mice lacking Apelin or APJ gene have impaired myocytecontractility (Charo, D. N. et al., Am. J. Physiol. Heart Circ.Physiol., 297(5):H1904-H1913 (2009)). Apelin knockout (KO) mice developprogressive cardiac dysfunction with aging and are more susceptible toHF in the model of trans-aortic constriction (TAC) (Kuba, K. et al.,Circ. Res., 101(4):e32-42 (2007)). The functional impairment in chronicHF is a result of prolonged demand on the heart and is associated withmaladaptive cardiac remodeling, manifested by the cardiac hypertrophy,increased inflammation and interstitial fibrosis which eventually leadto decrease in cardiac performance.

Acute administration of apelin increases cardiac output in rodents undernormal conditions and also in models of heart failure (Berry, M. F.,Circulation, 110(11 Suppl. 1):II187-II193 (2004)). Increased cardiacoutput is a result of direct augmentation of cardiac contractility andreduced peripheral vascular resistance in the arterial and venous beds(Ashley, E. A., Cardiovasc. Res., 65(1):73-82 (2005)). Reduction in thevascular resistance leads to lower pre-load and after-load on the heartand thus lesser work load (Cheng, X. et al., Eur. J. Pharmacol.,470(3):171-175 (2003)). Similar to rodent studies, acute infusion ofapelin to healthy human subjects and patients with heart failureproduces similar hemodynamic responses with increased cardiac output andincreased vasodilatory response in peripheral and coronary arteries(Japp, A. G. et al., Circulation, 121(16):1818-1827 (2010)).

The mechanisms underlying inotropic action of apelin are not wellunderstood, but appear to be distinct from clinically used β₁-adrenergicagonists (dobutamine) due to lack of increase in heart rate. Thevasodilatory action of apelin is primarily mediated via endothelialnitric oxide synthase pathways (Tatemoto, K., Regul. Pept.,99(2-3):87-92 (2001)). Apelin is induced under hypoxic conditions,promotes angiogenesis and has been shown to limit the infarct size inischemia-reperfusion models (Simpkin, J. C., Basic Res. Cardiol.,102(6):518-528 (2007)).

In addition to aforementioned studies evaluating acute administration ofapelin, several studies have clearly demonstrated beneficial effects ofprolonged administration of apelin in a number of chronic rodent modelsof HF, including the angiotensin II model, TAC model and rat Dahlsalt-sensitive model (Siddiquee, K. et al., J. Hypertens., 29(4):724-731(2011); Scimia, M. C. et al., Nature, 488(7411):394-398 (2012); Koguchi,W. et al., Circ. J., 76(1):137-144 (2012)). In these studies, prolongedapelin infusion reduced cardiac hypertrophy and cardiac fibrosis, andwas associated with improvement in cardiac performance.

Genetic evidence is also emerging that polymorphisms in the APJ gene areassociated with slower progression of HF (Sarzani, R. et al., J. Card.Fail., 13(7):521-529 (2007)). Importantly, while expression of APJ andapelin can be reduced or vary considerably with HF progression, thecardiovascular hemodynamic effects of apelin are sustained in patientswith developed HF and receiving standard of care therapy (Japp, A. G. etal., Circulation, 121(16):1818-1827 (2010)).

In summary, there is a significant amount of evidence to indicate thatAPJ receptor agonism plays a cardioprotective role in HF and would be ofpotential benefit to HF patients. Apelin's very short half life incirculation limits its therapeutic utility, and consequently, there is aneed for APJ receptor agonists with improved pharmacokinetic andsignaling profile while maintaining or enhancing the beneficial effectsof endogenous APJ agonist apelin.

SUMMARY OF THE INVENTION

The present invention provides 1,4-dihydropyrimidine-5-carboxamides, andtheir analogues thereof, which are useful as APJ agonists, includingstereoisomers, tautomers, pharmaceutically acceptable salts, or solvatesthereof.

The present invention also provides processes and intermediates formaking the compounds of the present invention or stereoisomers,tautomers, pharmaceutically acceptable salts, or solvates thereof.

The present invention also provides pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and at least one of thecompounds of the present invention or stereoisomers, tautomers,pharmaceutically acceptable salts, or solvates thereof.

The compounds of the invention may be used in the treatment and/orprophylaxis of multiple diseases or disorders associated with APJ, suchas heart failure, coronary artery disease, cardiomyopathy, diabetes andrelated conditions including but not limited to acute coronary syndrome,myocardial ischemia, hypertension, pulmonary hypertension, coronaryvasospasm, cerebral vasospasm, ischemia/reperfusion injury, angina,renal disease, metabolic syndrome and insulin resistance.

The compounds of the invention may be used in therapy.

The compounds of the invention may be used for the manufacture of amedicament for the treatment and/or prophylaxis of multiple diseases ordisorders associated with APJ.

The compounds of the invention can be used alone, in combination withother compounds of the present invention, or in combination with one ormore other agent(s).

Other features and advantages of the invention will be apparent from thefollowing detailed description and claims.

DETAILED DESCRIPTION OF THE INVENTION I. Compounds of the Invention

In a first aspect, the present disclosure provides, inter alia, acompound of Formula (I):

or a stereoisomer, an enantiomer, a diastereoisomer, a tautomer, apharmaceutically acceptable salt, a prodrug, or a solvate thereof,wherein:

-   alk is C₁₋₆ alkylene substituted with 0-5 R^(e);-   ring B is independently selected from C₃₋₆ cycloalkyl, C₃₋₆    cycloalkenyl, aryl, bicyclic carbocyclyl, and 6-membered heteroaryl;-   R¹, at each occurrence, is independently selected from H, halogen,    NO₂, —(CH₂)_(n)OR^(b), (CH₂)_(n)S(O)_(p)R_(c), —(CH₂)_(n)C(═O)R^(b),    —(CH₂)_(n)NR^(a)R^(a), —(CH₂)_(n)CN, —(CH₂)_(n)C(═O)NR^(a)R^(a),    —(CH₂)_(n)NR^(a)C(═O)R^(b), —(CH₂)_(n)NR^(a)C(═O)NR^(a)R^(a),    —(CH₂)_(n)NR^(a)C(═O)OR^(b), —(CH₂)_(n)OC(═O)NR^(a)R^(a),    —(CH₂)_(n)C(═O)OR^(b), (CH₂)_(n)S(O)_(p)NR^(a)R^(a),    —(CH₂)_(n)NR^(a)S(O)_(p)NR^(a)R^(a), —(CH₂)_(n)NR^(a)S(O)_(p)R_(c),    C₁₋₄ alkyl substituted with 0-3 R^(e), —(CH₂)_(n)—C₃₋₆ carbocyclyl    substituted with 0-3 R^(e), and —(CH₂)_(n)-heterocyclyl substituted    with 0-3 R^(e);-   R² is independently selected from C₁₋₅ alkyl substituted with 0-3    R^(e); C₂₋₅ alkenyl substituted with 0-3 R^(e), aryl substituted    with 0-3 R^(e), heteroaryl substituted with 0-3 R^(e), and C₃₋₆    cycloalkyl substituted with 0-3 R^(e); provided when R² is C₁₋₅    alkyl, the carbon atoms and the groups attached thereto except the    carbon atom attached to the pyrimidine ring may be replaced by O, N,    and S;-   R³ is independently selected from H and C₁₋₅ alkyl:-   R⁴ is independently selected from —(CR⁷R⁷)_(n)—R⁶, —(CR⁷R⁷)_(n)OR⁶,    —(CR⁷R⁷)_(n)S(O)_(p)R⁶, —(CR⁷R⁷)_(n)C(═O)R⁶, —(CR⁷R⁷)_(n)NR^(a)R⁶,    —(CR⁷R⁷)_(n)C(═O)NR^(a)R⁶, —(CR⁷R⁷)_(n)NR^(a)C(═O)R⁶,    —(CR⁷R⁷)_(n)S(O)_(p)NR^(a)R⁶, and —(CR⁷R⁷)_(n)NR^(a)S(O)_(p)R⁶;-   alternatively, R³ and R⁴ together with the nitrogen atom to which    they are both attached form a heterocyclic ring or a spiro    heterocyclic ring comprising carbon atoms and additional 1 to 4    heteroatoms selected from NR^(5a), O, and S and substituted with 0-5    R⁵;-   R⁵, at each occurrence, is independently at each occurrence,    selected from OH, halogen, —(CR⁷R⁷)_(n)—R⁶, —OR⁶, —S(O)_(p)R⁶,    —C(═O)R⁶, —NR^(a)R⁶, —C(═O)NR^(a)R⁶, —NR^(a)C(═O)R⁶,    —NR^(a)C(═O)OR⁶, —OC(═O)NR^(a)R⁶, —C(═O)OR⁶, —S(O)_(p)NR^(a)R⁶,    —NR^(a)S(O)_(p)NR^(a)R⁶, and —NR^(a)S(O)_(p)R⁶;-   R^(5a), at each occurrence, is independently selected from    —C(═O)OR⁶, C(═O)NR^(a)R⁶, —(CR⁷R⁷)_(n)—R⁶, —C(═O)—R⁶, and    —S(O)_(p)R⁶;-   R⁶, at each occurrence, is independently selected from    —(CR⁷R⁷)_(n)—C₃₋₁₀ carbocyclyl and —(CR⁷R⁷)_(n)-heteroaryl, each    substituted with 0-3 R⁸;-   R⁷, at each occurrence, is independently selected from H, C₁₋₄    alkyl, and (CH₂)_(n)—C₃₋₁₂ carbocyclyl substituted with 0-3 R^(e);-   R⁸, at each occurrence, is independently selected from H, halogen,    —(CH₂)_(n)OR^(b), (CH₂)_(n)S(O)_(p)R_(c), —(CH₂)_(n)C(═O)R^(b),    —(CH₂)_(n)NR^(a)R^(a), —(CH₂)_(n)CN, —(CH₂)_(n)C(═O)NR^(a)R^(a),    —(CH₂)_(n)NR^(a)C(═O)R^(b), —(CH₂)_(n)NR^(a)C(═O)NR^(a)R^(a),    —(CH₂)_(n)NR^(a)C(═O)OR^(b), —(CH₂)_(n)OC(═O)NR^(a)R^(a),    —(CH₂)_(n)C(═O)OR^(b), (CH₂)_(n)S(O)_(p)NR^(a)R^(a),    —(CH₂)_(n)NR^(a)S(O)_(p)NR^(a)R^(a), —(CH₂)_(n)NR^(a)S(O)_(p)R_(c),    C₁₋₅ alkyl substituted with 0-3 R^(e), (CH₂)_(n)—C₃₋₆ carbocyclyl    substituted with 0-3 R^(e), and —(CH₂)_(n)-heterocyclyl substituted    with 0-3 R^(e);-   R^(a), at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5    R^(e), C₂₋₆ alkynyl substituted with 0-5 R^(e),    —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e), and    —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e); or R^(a) and    R^(a) together with the nitrogen atom to which they are both    attached form a heterocyclic ring substituted with 0-5 R^(e);-   R^(b), at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5    R^(e), C₂₋₆ alkynyl substituted with 0-5 R^(e),    —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e), and    —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e);-   R_(c), at each occurrence, is independently selected from C₁₋₆ alkyl    substituted with 0-5 R^(e), C₂₋₆alkenyl substituted with 0-5 R^(e),    C₂₋₆alkynyl substituted with 0-5 R^(e), C₃₋₆carbocyclyl, and    heterocyclyl;-   R^(e), at each occurrence, is independently selected from C₁₋₆ alkyl    substituted with 0-5 R_(f), C₂₋₆ alkenyl, C₂₋₆ alkynyl,    —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)—C₄₋₆ heterocyclyl,    —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, F, Cl, Br, CN, NO₂, ═O,    CO₂H, —(CH₂)_(n)OR_(f), S(O)_(p)R^(f), C(═O)NR^(f)R_(f),    NR^(f)C(═O)R^(f), S(O)_(p)NR^(f)R_(f), NR^(f)S(O)_(p)R^(f),    NR^(f)C(═O)OR^(f), OC(═O)NR^(f)R_(f) and —(CH₂)_(n)NR^(f)R_(f);-   R^(f), at each occurrence, is independently selected from H, F, Cl,    Br, CN, OH, C₁₋₅alkyl (optionally substituted with halogen and OH),    C₃₋₆ cycloalkyl, and phenyl, or R^(f) and R^(f) together with the    nitrogen atom to which they are both attached form a heterocyclic    ring optionally substituted with C₁₋₄alkyl;-   n, at each occurrence, is independently selected from zero, 1, 2, 3,    and 4; and-   p, at each occurrence, is independently selected from zero, 1, and    2.

In a second aspect, the present disclosure provides a compound ofFormula (I), or a stereoisomer, an enantiomer, a diastereoisomer, atautomer, a pharmaceutically acceptable salt, a prodrug, or a solvatethereof, within the scope of the first aspect, wherein:

-   R¹, at each occurrence, is independently selected from H, F, Cl, Br,    NO₂, —(CH₂)_(n)OR^(b), —(CH₂)_(n)C(═O)R^(b), —(CH₂)_(n)NR^(a)R^(a),    —(CH₂)_(n)CN, —(CH₂)_(n)C(═O)NR^(a)R^(a),    —(CH₂)_(n)NR^(a)C(═O)R^(b), C₁₋₄ alkyl substituted with 0-3 R^(e)    and C₃₋₆ cycloalkyl substituted with 0-3 R^(e);-   R² is independently selected from C₁₋₅ alkyl substituted with 0-3    R^(e); C₂₋₅ alkenyl, aryl substituted with 0-3 R^(e), heteroaryl    substituted with 0-3 R^(e), C₃₋₆ cycloalkyl, —(CH₂)₁₋₄OC₁₋₅alkyl,    —(CH₂)₁₋₄NHC₁₋₅alkyl, and —(CH₂)₁₋₃OC₃₋₆cycloalkyl;-   R³ and R⁴ together with the nitrogen atom to which they are both    attached form a heterocyclic ring or a spiro heterocyclic ring    selected from

-   R⁵, at each occurrence, is independently selected from OH,    —(CH₂)_(n)—R⁶, —(CR⁷R⁷)_(n)—R⁶, OR⁶, —S(O)_(p)R⁶, —C(═O)R⁶,    —NR^(a)R⁶, —C(═O)NR^(a)R⁶, —NR^(a)C(═O)R⁶, —NR^(a)C(═O)OR⁶,    —OC(═O)NR^(a)R⁶, —C(═O)OR⁶, —S(O)_(p)NR^(a)R⁶,    —NR^(a)S(O)_(p)NR^(a)R⁶, and —NR^(a)S(O)_(p)R⁶;-   R^(5a), at each occurrence, is independently selected from    —C(═O)OR⁶, C(═O)NR^(a)R⁶, —(CR⁷R⁷)_(n)—R⁶, —C(═O)—R⁶, and    —S(O)_(p)R⁶;-   R⁶, at each occurrence, is independently selected from    —(CR⁷R⁷)_(n)-aryl, —(CR⁷R⁷)_(n)—C₃₋₆ cycloalkyl, and    —(CR⁷R⁷)_(n)-heteroaryl, each substituted with 0-3 R⁸;-   R⁷, at each occurrence, is independently selected from H, C₁₋₄    alkyl, and (CH₂)_(n)—C₃₋₁₂ carbocyclyl substituted with 0-3 R^(e);-   R⁸, at each occurrence, is independently selected from H, F, Cl, Br,    —OR^(b), —(CH₂)_(n)C(═O)R^(b), —(CH₂)_(n)C(═O)OR^(b),    —(CH₂)_(n)NR^(a)R^(a), CN, —(CH₂)_(n)C(═O)NR^(a)R^(a),    —NHC(═O)OR^(b), C₁₋₄ alkyl substituted with 0-3 R^(e),    (CH₂)_(n)—C₃₋₆ carbocyclyl substituted with 0-3 R^(e), and    —(CH₂)_(n)-heterocyclyl substituted with 0-3 R^(e);-   R^(a), at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl    substituted with 0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted    with 0-5 R^(e); or R^(a) and R^(a) together with the nitrogen atom    to which they are both attached form a heterocyclic ring substituted    with 0-5 R^(e);-   R^(b), at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5    R^(e), C₂₋₆ alkynyl substituted with 0-5 R^(e),    —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e), and    —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e);-   R^(e), at each occurrence, is independently selected from C₁₋₆ alkyl    substituted with 0-5 R_(f), C₂₋₆ alkenyl, C₂₋₆ alkynyl,    —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)—C₄₋₆ heterocyclyl,    —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, F, Cl, Br, CN, NO₂, ═O,    CO₂H, —(CH₂)_(n)OR_(f), S(O)_(p)R^(f), C(═O)NR^(f)R_(f),    NR^(f)C(═O)R^(f), S(O)_(p)NR^(f)R_(f), NR^(f)S(O)_(p)R^(f),    NR^(f)C(═O)OR^(f), OC(═O)NR^(f)R_(f) and —(CH₂)_(n)NR^(f)R_(f);-   R^(f), at each occurrence, is independently selected from H, F, Cl,    Br, CN, OH, C₁₋₅alkyl (optionally substituted with halogen and OH),    C₃₋₆ cycloalkyl, and phenyl;-   n, at each occurrence, is independently selected from zero, 1, 2, 3,    and 4; and-   p, at each occurrence, is independently selected from zero, 1, and    2.

In a third aspect, the present disclosure provides a compound of Formula(II):

or a stereoisomer, an enantiomer, a diastereoisomer, a tautomer, apharmaceutically acceptable salt, a prodrug, or a solvate thereof,within the scope of the first or second aspect, wherein:

ring B is independently selected from

-   R¹, at each occurrence, is independently selected from H, F, Cl, OH,    CN, OC₁₋₄ alkyl, and C₃₋₆ cycloalkyl;-   R² is independently selected from C₁₋₅ alkyl substituted with 0-3    R^(e); C₂₋₅ alkenyl, aryl substituted with 0-3 R^(e), heteroaryl    substituted with 0-3 R^(e), C₃₋₆ cycloalkyl, —(CH₂)₁₋₄OC₁₋₅alkyl,    and —(CH₂)₁₋₃OC₃₋₆cycloalkyl;-   R³ and R⁴ together with the nitrogen atom to which they are both    attached form a heterocyclic ring selected from

-   R⁵, at each occurrence, is independently selected from OH,    —(CH₂)_(n)—R⁶, —(CR⁷R⁷)_(n)—R⁶, —OR⁶, —S(O)_(p)R⁶, —C(═O)R⁶,    —NR^(a)R⁶, —C(═O)NR^(a)R⁶, —NR^(a)C(═O)R⁶, —NR^(a)C(═O)OR⁶,    —OC(═O)NR^(a)R⁶, —C(═O)OR⁶, —S(O)_(p)NR^(a)R⁶,    —NR^(a)S(O)_(p)NR^(a)R⁶, and —NR^(a)S(O)_(p)R⁶;-   R^(5a), at each occurrence, is independently selected from    —C(═O)OR⁶, C(═O)NR^(a)R⁶, —(CR⁷R⁷)_(n)—R⁶, —C(═O)—R⁶, and    —S(O)_(p)R⁶;-   R⁶, at each occurrence, is independently selected from    —(CR⁷R⁷)_(n)-aryl, —(CR⁷R⁷)_(n)—C₃₋₆ cycloalkyl, and    —(CR⁷R⁷)_(n)-heteroaryl, each substituted with 0-3 R⁸;-   R⁷, at each occurrence, is independently selected from H, C₁₋₄    alkyl, and (CH₂)_(n)—C₃₋₁₂ carbocyclyl substituted with 0-3 R^(e);-   R⁸, at each occurrence, is independently selected from H, F, Cl, Br,    —OR^(b), —(CH₂)_(n)C(═O)R^(b), —(CH₂)_(n)C(═O)OR^(b),    —(CH₂)_(n)NR^(a)R^(a), CN, —(CH₂)_(n)C(═O)NR^(a)R^(a), C₁₋₄ alkyl    substituted with 0-3 R^(e), (CH₂)_(n)—C₃₋₆ carbocyclyl substituted    with 0-3 R^(e), and —(CH₂)_(n)-heterocyclyl substituted with 0-3    R^(e);-   R^(a), at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl    substituted with 0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted    with 0-5 R^(e); or R^(a) and R^(a) together with the nitrogen atom    to which they are both attached form a heterocyclic ring substituted    with 0-5 R^(e);-   R^(b), at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5    R^(e), C₂₋₆ alkynyl substituted with 0-5 R^(e),    —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e), and    —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e);-   R^(e), at each occurrence, is independently selected from C₁₋₆ alkyl    (optionally substituted with F and Cl), OH, OCH₃, OCF₃,    —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)—C₄₋₆ heterocyclyl,    —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, F, Cl, Br, CN, NO₂, ═O,    CO₂H; and-   n, at each occurrence, is independently selected from zero, 1, 2, 3,    and 4.

In a fourth aspect, the present disclosure provides a compound ofFormula (II), or a stereoisomer, an enantiomer, a diastereoisomer, atautomer, a pharmaceutically acceptable salt, a prodrug, or a solvatethereof, within the scope of any of the first, second and third aspects,wherein:

-   R¹, at each occurrence, is independently selected from H, F, Cl, OH,    and OC₁₋₄ alkyl;-   R² is independently selected from C₁₋₅ alkyl substituted with 0-3    R^(e); C₂₋₅ alkenyl, phenyl substituted with 0-3 R^(e), 6-membered    heteroaryl substituted with 0-3 R^(e), C₃₋₆ cycloalkyl; and    CH₂O(CH₂)₁₋₃CH₃;-   R³ and R⁴ together with the nitrogen atom to which they are both    attached form a heterocyclic ring selected from

-   R⁵ is independently at each occurrence, selected from OH,

-   R⁸, at each occurrence, is independently selected from H, F, Cl, Br,    —OCH₃, —OCF₃, ═O, CN, CH₃, CF₃—(CH₂)_(n)-aryl, —(CH₂)_(n)—C₃₋₆    cycloalkyl substituted with 0-3 R^(e), and —(CH₂)_(n)-heterocyclyl    substituted with 0-3 R^(e);-   R^(8a), at each occurrence, is independently selected from H, CH₃,    aryl substituted with 0-3 R^(e), and heterocyclyl substituted with    0-3 R^(e);-   R^(a), at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl    substituted with 0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted    with 0-5 R^(e);-   R^(e), at each occurrence, is independently selected from C₁₋₆ alkyl    (optionally substituted with F and Cl), OH, OCH₃, OCF₃,    —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)—C₄₋₆ heterocyclyl,    —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, F, Cl, Br, CN, NO₂, ═O,    CO₂H; and-   n, at each occurrence, is independently selected from zero, 1, 2,    and 3.

In a fifth aspect, the present disclosure provides a compound of Formula(III):

or a stereoisomer, an enantiomer, a diastereoisomer, a tautomer, apharmaceutically acceptable salt, a prodrug, or a solvate thereof,within the scope of the first or second aspect, wherein:

ring B is independently selected from

-   R¹, at each occurrence, is independently selected from H, F, Cl, OH,    and OC₁₋₄ alkyl;-   R² is independently selected from C₁₋₅ alkyl substituted with 0-3    R^(e); C₂₋₅ alkenyl, phenyl substituted with 0-1 R^(e), 6-membered    heteroaryl substituted with 0-1 R^(e), and C₃₋₆ cycloalkyl; and    CH₂O(CH₂)₁₋₃CH₃;-   R⁵ is independently at each occurrence, selected from OH,

-   R⁸, at each occurrence, is independently selected from H, F, Cl, Br,    —OCH₃, —OCF₃, ═O, CN, CH₃, CF₃, —C(═O)NH₂, —(CH₂)_(n)-aryl    substituted with 0-3 R^(e), —(CH₂)_(n)—C₃₋₆ cycloalkyl substituted    with 0-3 R^(e), and —(CH₂)_(n)-heterocyclyl substituted with 0-3    R^(e);-   R^(8a), at each occurrence, is independently selected from H, CH₃,    aryl substituted with 0-3 R^(e), and heterocyclyl substituted with    0-3 R^(e);-   R^(a), at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl    substituted with 0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted    with 0-5 R^(e);-   R^(e), at each occurrence, is independently selected from C₁₋₆ alkyl    (optionally substituted with F and Cl), OH, OCH₃, OCF₃,    —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)—C₄₋₆ heterocyclyl,    —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, F, Cl, Br, CN, NO₂, ═O,    CO₂H; and-   n, at each occurrence, is independently selected from zero, 1, 2,    and 3.

In a sixth aspect, the present disclosure provides a compound of Formula(III), or a stereoisomer, an enantiomer, a diastereoisomer, a tautomer,a pharmaceutically acceptable salt, a prodrug, or a solvate thereof,within the scope of any of the first, second and third aspects, wherein:

-   R¹, at each occurrence, is independently selected from F, Cl, OH,    —OCH₃, and —OCD₃;-   R² is independently selected from C₁₋₅ alkyl substituted with 0-3    R^(e); C₂₋₅ alkenyl, phenyl substituted with 0-3 R^(e), 6-membered    heteroaryl substituted with 0-3 R^(e), and C₃₋₆ cycloalkyl; and    CH₂O(CH₂)₁₋₃CH₃;-   R³ and R⁴ together with the nitrogen atom to which they are both    attached form

-   R⁵, at each occurrence, is independently at each occurrence,    selected from OH, F, and Cl;-   R^(5a) is independently at each occurrence, selected from

-   R⁸, at each occurrence, is independently selected from H, F, Cl, Br,    —OCH₃, —O(CH₂)₁₋₃OCH₃, —OCF₃, ═O, CN, CH₃, CF₃—(CH₂)_(n)-aryl,    —(CH₂)_(n)—C₃₋₆ cycloalkyl substituted with 0-3 R^(e), and    —(CH₂)_(n)-heterocyclyl substituted with 0-3 R^(e);-   R^(8a), at each occurrence, is independently selected from H, CH₃,    aryl substituted with 0-3 R^(e), and heterocyclyl substituted with    0-3 R^(e);-   R^(a), at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl    substituted with 0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted    with 0-5 R^(e);-   R^(b), at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5    R^(e), C₂₋₆ alkynyl substituted with 0-5 R^(e),    —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e), and    —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e);-   R^(e), at each occurrence, is independently selected from C₁₋₆ alkyl    (optionally substituted with F and Cl), OH, OCH₃, OCF₃,    —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)—C₄₋₆ heterocyclyl,    —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, F, Cl, Br, CN, NO₂, ═O,    CO₂H; and-   n, at each occurrence, is independently selected from zero, 1, 2,    and 3.

In a seventh aspect, the present disclosures provides a compound ofFormula (I), or a stereoisomer, an enantiomer, a diastereoisomer, atautomer, a pharmaceutically acceptable salt, a prodrug, or a solvatethereof, within the scope of any of the first, second and third aspects,wherein:

-   R¹, at each occurrence, is independently selected from —CH₂OH,    —OCH₃, —OCF₃, —OCD₃—OCH₂Ph, —C(═O)NR^(a)R^(a), —NR^(a)R^(a), CH₃,    CH₂CH₃, CH(CH₃)₂, and cyclopropyl;-   R² is independently selected from C₁₋₄ alkyl substituted with 0-3    R^(e); C₂₋₄ alkenyl, phenyl substituted with 0-3 R^(e), 6-membered    heteroaryl substituted with 0-3 R^(e), C₃₋₆ cycloalkyl, and    CH₂O(CH₂)₁₋₃CH₃;-   R³ is independently selected from H and C₁₋₄ alkyl:-   R⁴ is independently selected from —(CHR⁷)₁₋₄—R⁶, —(CH₂)₁₋₃OR⁶,    —(CH₂)₁₋₃NHR⁶, and —(CH₂)₀₋₃NHC(═O)R⁶;-   R⁶, at each occurrence, is independently selected from    —(CR⁷R⁷)_(n)-aryl, —(CR⁷R⁷)_(n)—C₃₋₆ cycloalkyl, and    —(CR⁷R⁷)_(n)-heteroaryl, each substituted with 0-3 R⁸;-   R⁷, at each occurrence, is independently selected from H, C₁₋₄    alkyl, and aryl;-   R⁸, at each occurrence, is independently selected from H, F, Cl,    —OR^(b), —NR^(a)R^(a), C₁₋₄ alkyl substituted with 0-3 R^(e), phenyl    substituted with 0-3 R^(e), and heterocyclyl substituted with 0-3    R^(e);-   R^(a), at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0-5 R^(e), —(CH₂)_(n)-phenyl substituted with    0-5 R^(e), and —(CH₂)_(n)-heteroaryl substituted with 0-5 R^(e);-   R^(b), at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl    substituted with 0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted    with 0-5 R^(e);-   R^(e), at each occurrence, is independently selected from C₁₋₆ alkyl    (optionally substituted with F and Cl), OH, OCH₃, OCF₃,    —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)—C₄₋₆ heterocyclyl,    —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, F, Cl, Br, CN, NO₂, ═O,    CO₂H; and-   n is independently selected from zero, 1, 2, 3, and 4.

In an eighth aspect, the present disclosure provides a compound, or astereoisomer, an enantiomer, a diastereoisomer, a tautomer, apharmaceutically acceptable salt, a prodrug, or a solvate thereof,within the scope of the first, second, and third aspects, wherein:

-   R¹, at each occurrence, is independently selected from —CH₂OH,    —OCH₃, —OCF₃, OCH₂Ph, —C(═O)NR^(a)R^(a), —NR^(a)R^(a), CH₃, CH₂CH₃,    CH(CH₃)₂, and cyclopropyl;-   R² is independently selected from C₁₋₅ alkyl substituted with 0-3    R^(e); C₂₋₅ alkenyl, phenyl substituted with 0-3 R^(e), 6-membered    heteroaryl substituted with 0-3 R^(e), C₃₋₆ cycloalkyl and    CH₂O(CH₂)₁₋₃CH₃;-   R³ and R⁴ are independently selected from C₁₋₅ alkyl substituted    with 0-3 R⁶; —(CH₂)_(n)—C₃₋₆ carbocyclyl substituted with 0-3 R⁶,    and —(CH₂)_(n)-heterocyclyl substituted with 0-3 R⁶;-   R⁶, at each occurrence, is independently selected from H, halogen,    —(CH₂)_(n)OR^(b), —(CH₂)_(n)NR^(a)R^(a), —(CH₂)_(n)C(═O)NR^(a)R^(a),    —(CH₂)_(n)NR^(a)C(═O)R^(b), (CH₂)_(n)NR^(a)C(═O)OR^(b),    —(CH₂)_(n)OC(═O)NR^(a)R^(a), —(CH₂)_(n)C(═O)OR^(b),    (CH₂)_(n)S(O)_(p)NR^(a)R^(a), —(CH₂)_(n)NR^(a)S(O)_(p)NR^(a)R^(a),    C₁₋₅ alkyl substituted with 0-3 R^(e), phenyl substituted with 0-3    R^(e), and heterocyclyl substituted with 0-3 R^(e);-   R^(a), at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0-5 R^(e), —(CH₂)_(n)-phenyl substituted with    0-5 R^(e), and —(CH₂)_(n)-heteroaryl substituted with 0-5 R^(e);-   R^(b), at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl    substituted with 0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted    with 0-5 R^(e);-   R^(e), at each occurrence, is independently selected from C₁₋₆ alkyl    (optionally substituted with F and Cl), OH, OCH₃, OCF₃,    —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)—C₄₋₆ heterocyclyl,    —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, F, Cl, Br, CN, NO₂, ═O,    CO₂H; and-   n, at each occurrence, is independently selected from zero, 1, 2, 3,    and 4.

In a ninth aspect, the present disclosure provides a compound selectedfrom the exemplified examples or stereoisomers, enantiomers,diastereoisomers, tautomers, pharmaceutically acceptable salts,prodrugs, or solvates thereof.

In another aspect, the present disclosure provides a compound selectedfrom any subset list of compounds within the scope of the eighth aspect.

In another aspect, the present disclosure provides compounds of Formula(I), or stereoisomers, enantiomers, diastereoisomers, tautomers,pharmaceutically acceptable salts, prodrugs, or solvates thereof,wherein:

-   alk is C₁₋₆ alkylene substituted with 0-5 R^(e);-   ring B is independently selected from C₃₋₆ cycloalkyl, C₃₋₆    cycloalkenyl, aryl, bicyclic carbocyclyl, and 6-membered heteroaryl;-   R¹, at each occurrence, is independently selected from H, halogen,    NO₂, —(CH₂)_(n)OR^(b), (CH₂)_(n)S(O)_(p)R_(c), —(CH₂)_(n)C(═O)R^(b),    —(CH₂)_(n)NR^(a)R^(a), —(CH₂)_(n)CN, —(CH₂)_(n)C(═O)NR^(a)R^(a),    —(CH₂)_(n)NR^(a)C(═O)R^(b), —(CH₂)_(n)NR^(a)C(═O)NR^(a)R^(a),    —(CH₂)_(n)NR^(a)C(═O)OR^(b), —(CH₂)_(n)OC(═O)NR^(a)R^(a),    —(CH₂)_(n)C(═O)OR^(b), (CH₂)_(n)S(O)_(p)NR^(a)R^(a),    —(CH₂)_(n)NR^(a)S(O)_(p)NR^(a)R^(a), —(CH₂)_(n)NR^(a)S(O)_(p)R_(c),    C₁₋₄ alkyl substituted with 0-3 R^(e), —(CH₂)_(n)—C₃₋₆ carbocyclyl    substituted with 0-3 R^(e), and —(CH₂)_(n)-heterocyclyl substituted    with 0-3 R^(e);-   R² is independently selected from C₁₋₁₀ alkyl substituted with 0-3    R^(e); C₂₋₅ alkenyl substituted with 0-3 R^(e), aryl substituted    with 0-3 R^(e), heteroaryl substituted with 0-3 R^(e), and C₃₋₆    cycloalkyl substituted with 0-3 R^(e); provided when R² is C₁₋₁₀    alkyl, the carbon atoms and the groups attached thereto except the    carbon atom attached to the pyrimidine ring may be replaced by O, N,    and S;-   R³ is independently selected from H and C₁₋₅ alkyl:-   R⁴ is independently selected from —(CR⁷R⁷)_(n)—R⁶, —(CR⁷R⁷)_(n)OR⁶,    —(CR⁷R⁷)_(n)S(O)_(p)R⁶, —(CR⁷R⁷)_(n)C(═O)R⁶, —(CR⁷R⁷)_(n)NR^(a)R⁶,    —(CR⁷R⁷)_(n)NR^(a)C(═O)R⁶, —(CR⁷R⁷)_(n)S(O)_(p)NR^(a)R⁶, and    —(CR⁷R⁷)_(n)NR^(a)S(O)_(p)R⁶;-   alternatively, R³ and R⁴ together with the nitrogen atom to which    they are both attached form a heterocyclic ring or a spiro    heterocyclic ring comprising carbon atoms and additional 1 to 4    heteroatoms selected from NR^(a), O, and S and substituted with 0-5    R⁵;-   R⁵, at each occurrence, is independently selected from OH, halogen,    —(CR⁷R⁷)_(n)—R⁶, —OR⁶, —S(O)_(p)R⁶, —C(═O)R⁶, —NR^(a)R⁶,    —C(═O)NR^(a)R⁶, —NR^(a)C(═O)R⁶, —NR^(a)C(═O)OR⁶, —OC(═O)NR^(a)R⁶,    —C(═O)OR⁶, —S(O)_(p)NR^(a)R⁶, —NR^(a)S(O)_(p)NR^(a)R⁶, and    —NR^(a)S(O)_(p)R⁶;-   R^(5a), at each occurrence is independently selected from —C(═O)OR⁶,    C(═O)NR^(a)R⁶, —(CR⁷R⁷)_(n)—R⁶, —C(═O)—R⁶, and —S(O)_(p)R⁶;-   R⁶, at each occurrence, is independently selected from    —(CR⁷R⁷)_(n)—C₃₋₁₀ carbocyclyl and —(CR⁷R⁷)_(n)-heteroaryl, each    substituted with 0-3 R⁸;-   R⁷, at each occurrence, is independently selected from H, C₁₋₄    alkyl, and (CH₂)_(n)—C₃₋₁₂ carbocyclyl substituted with 0-3 R^(e);-   R⁸, at each occurrence, is independently selected from H, halogen,    —(CH₂)_(n)OR^(b), ═O, (CH₂)_(n)S(O)_(p)R_(c), —(CH₂)_(n)C(═O)R^(b),    —(CH₂)_(n)NR^(a)R^(a), —(CH₂)_(n)CN, —(CH₂)_(n)C(═O)NR^(a)R^(a),    —(CH₂)_(n)NR^(a)C(═O)R^(b), —(CH₂)_(n)NR^(a)C(═O)NR^(a)R^(a),    —(CH₂)_(n)NR^(a)C(═O)OR^(b), —(CH₂)_(n)OC(═O)NR^(a)R^(a),    —(CH₂)_(n)C(═O)OR^(b), (CH₂)_(n)S(O)_(p)NR^(a)R^(a),    —(CH₂)_(n)NR^(a)S(O)_(p)NR^(a)R^(a), —(CH₂)_(n)NR^(a)S(O)_(p)R_(c),    C₁₋₅ alkyl substituted with 0-3 R^(e), (CH₂)_(n)—C₃₋₆ carbocyclyl    substituted with 0-3 R^(e), and —(CH₂)_(n)-heterocyclyl substituted    with 0-3 R^(e);-   R^(a), at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5    R^(e), C₂₋₆ alkynyl substituted with 0-5 R^(e),    —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e), and    —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e); or R^(a) and    R^(a) together with the nitrogen atom to which they are both    attached form a heterocyclic ring substituted with 0-5 R^(e);-   R^(b), at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5    R^(e), C₂₋₆ alkynyl substituted with 0-5 R^(e),    —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e), and    —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e);-   R^(c), at each occurrence, is independently selected from C₁₋₆ alkyl    substituted with 0-5 R^(e), C₂₋₆alkenyl substituted with 0-5 R^(e),    C₂₋₆alkynyl substituted with 0-5 R^(e), C₃₋₆carbocyclyl, and    heterocyclyl;-   R^(e), at each occurrence, is independently selected from F, Cl, Br,    CN, NO₂, ═O, CO₂H, C₁₋₆ alkyl substituted with 0-5 R_(f), C₂₋₆    alkenyl, C₂₋₆ alkynyl, —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)—C₄₋₆    heterocyclyl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl,    —(CH₂)_(n)OR_(f), S(O)_(p)R_(f), C(═O)NR^(f)R^(f), NR^(f)C(═O)R^(f),    S(O)_(p)NR^(f)R^(f), NR^(f)S(O)_(p)R^(f), NR^(f)C(═O)OR^(f),    OC(═O)NR^(f)R_(f) and —(CH₂)_(n)NR^(f)R_(f);-   R^(f), at each occurrence, is independently selected from H, F, Cl,    Br, CN, OH, C₁₋₅alkyl (optionally substituted with halogen and OH),    C₃₋₆ cycloalkyl, and phenyl, or R^(f) and R^(f) together with the    nitrogen atom to which they are both attached form a heterocyclic    ring optionally substituted with C₁₋₄alkyl;-   n, at each occurrence, is independently selected from zero, 1, 2, 3,    and 4; and-   p, at each occurrence, is independently selected from zero, 1, and    2.

In another aspect, the present disclosure provides compounds of Formula(I), or stereoisomers, enantiomers, diastereoisomers, tautomers,pharmaceutically acceptable salts, prodrugs, or solvates thereof,wherein:

-   R¹, at each occurrence, is independently selected from H, F, Cl, Br,    NO₂, —(CH₂)_(n)OR^(b), —(CH₂)_(n)C(═O)R^(b), —(CH₂)_(n)NR^(a)R^(a),    —(CH₂)_(n)CN, —(CH₂)_(n)C(═O)NR^(a)R^(a),    —(CH₂)_(n)NR^(a)C(═O)R^(b), C₁₋₄ alkyl substituted with 0-3 R^(e)    and C₃₋₆ cycloalkyl substituted with 0-3 R^(e);-   R² is independently selected from C₁₋₅ alkyl substituted with 0-3    R^(e); C₂₋₅ alkenyl, aryl substituted with 0-3 R^(e), heteroaryl    substituted with 0-3 R^(e), C₃₋₆ cycloalkyl, —(CH₂)₁₋₄OC₁₋₅alkyl,    —(CH₂)₁₋₄NHC₁₋₅alkyl, and —(CH₂)₁₋₃OC₃₋₆cycloalkyl;-   R³ and R⁴ together with the nitrogen atom to which they are both    attached form a heterocyclic ring or a spiro heterocyclic ring    selected from

-   R⁵, at each occurrence, is independently selected from OH,    —(CH₂)_(n)—R⁶, —(CR⁷R⁷)_(n)—R⁶, OR⁶, —S(O)_(p)R⁶, —C(═O)R⁶,    —NR^(a)R⁶, —C(═O)NR^(a)R⁶, —NR^(a)C(═O)R⁶, —NR^(a)C(═O)OR⁶,    —OC(═O)NR^(a)R⁶, —C(═O)OR⁶, —S(O)_(p)NR^(a)R⁶,    —NR^(a)S(O)_(p)NR^(a)R⁶, and —NR^(a)S(O)_(p)R⁶;-   R^(5a), at each occurrence, is independently selected from    —C(═O)OR⁶, C(═O)NR^(a)R⁶, —(CR⁷R⁷)_(n)—R⁶, —C(═O)—R⁶, and    —S(O)_(p)R⁶;-   R⁶, at each occurrence, is independently selected from    —(CR⁷R⁷)_(n)-aryl, —(CR⁷R⁷)_(n)—C₃₋₆ cycloalkyl, and    —(CR⁷R⁷)_(n)-heteroaryl, each substituted with 0-3 R⁸;-   R⁷, at each occurrence, is independently selected from H, C₁₋₄    alkyl, and (CH₂)_(n)—C₃₋₁₂ carbocyclyl substituted with 0-3 R^(e);-   R⁸, at each occurrence, is independently selected from H, F, Cl, Br,    —OR^(b), —(CH₂)_(n)C(═O)R^(b), —(CH₂)_(n)C(═O)OR^(b),    —(CH₂)_(n)NR^(a)R^(a), CN, —(CH₂)_(n)C(═O)NR^(a)R^(a),    —NHC(═O)OR^(b), C₁₋₄ alkyl substituted with 0-3 R^(e),    (CH₂)_(n)—C₃₋₆ carbocyclyl substituted with 0-3 R^(e), and    —(CH₂)_(n)-heterocyclyl substituted with 0-3 R^(e);-   R^(a), at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl    substituted with 0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted    with 0-5 R^(e); or R^(a) and R^(a) together with the nitrogen atom    to which they are both attached form a heterocyclic ring substituted    with 0-5 R^(e);-   R^(b), at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5    R^(e), C₂₋₆ alkynyl substituted with 0-5 R^(e),    —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e), and    —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e);-   R^(e), at each occurrence, is independently selected from F, Cl, Br,    CN, NO₂, ═O, CO₂H, C₁₋₆ alkyl substituted with 0-5 R_(f), C₂₋₆    alkenyl, C₂₋₆ alkynyl, —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)—C₄₋₆    heterocyclyl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl,    —(CH₂)_(n)OR_(f), S(O)_(p)R, C(═O)NR^(f)R^(f), NR^(f)C(═O)R^(f),    S(O)_(p)NR^(f)R^(f), NR^(f)S(O)_(p)R^(f), NR^(f)C(═O)OR^(f),    OC(═O)NR^(f)R_(f) and —(CH₂)_(n)NR^(f)R_(f);-   R^(f), at each occurrence, is independently selected from H, F, Cl,    Br, CN, OH, C₁₋₅alkyl (optionally substituted with halogen and OH),    C₃₋₆ cycloalkyl, and phenyl;-   n, at each occurrence, is independently selected from zero, 1, 2, 3,    and 4; and-   p, at each occurrence, is independently selected from zero, 1, and    2.

In another aspect, the present disclosure provides compounds of Formula(II), or stereoisomers, enantiomers, diastereoisomers, tautomers,pharmaceutically acceptable salts, prodrugs, or solvates thereof,wherein:

-   ring B is independently selected from

-   R¹, at each occurrence, is independently selected from H, F, Cl, OH,    CN, C₁₋₄ alkyl, OC₁₋₄ alkyl, and C₃₋₆ cycloalkyl;-   R² is independently selected from C₁₋₅ alkyl substituted with 0-3    R^(e); C₂₋₅ alkenyl, aryl substituted with 0-3 R^(e), heteroaryl    substituted with 0-3 R^(e), C₃₋₆ cycloalkyl, —(CH₂)₁₋₄OC₁₋₅alkyl,    and —(CH₂)₁₋₃OC₃₋₆cycloalkyl;-   R³ and R⁴ together with the nitrogen atom to which they are both    attached form a heterocyclic ring selected from

-   R⁵, at each occurrence, is independently selected from OH,    —(CH₂)_(n)—R⁶, —(CR⁷R⁷)_(n)—R⁶, —OR⁶, —S(O)_(p)R⁶, —C(═O)R⁶,    —NR^(a)R⁶, —C(═O)NR^(a)R⁶, —NR^(a)C(═O)R⁶, —NR^(a)C(═O)OR⁶,    —OC(═O)NR^(a)R⁶, —C(═O)OR⁶, —S(O)_(p)NR^(a)R⁶,    —NR^(a)S(O)_(p)NR^(a)R⁶, and —NR^(a)S(O)_(p)R⁶;-   R^(5a), at each occurrence, is independently selected from    —C(═O)OR⁶, C(═O)NR^(a)R⁶, —(CR⁷R⁷)_(n)—R⁶, —C(═O)—R⁶, and    —S(O)_(p)R⁶;-   R⁶, at each occurrence, is independently selected from    —(CR⁷R⁷)_(n)-aryl, —(CR⁷R⁷)_(n)—C₃₋₆ cycloalkyl, and    —(CR⁷R⁷)_(n)-heteroaryl, each substituted with 0-3 R⁸;-   R⁷, at each occurrence, is independently selected from H, C₁₋₄    alkyl, and (CH₂)_(n)—C₃₋₁₂ carbocyclyl substituted with 0-3 R^(e);-   R⁸, at each occurrence, is independently selected from H, F, Cl, Br,    —OR^(b), —(CH₂)_(n)C(═O)R^(b), —(CH₂)_(n)C(═O)OR^(b),    —(CH₂)_(n)NR^(a)R^(a), CN, —(CH₂)_(n)C(═O)NR^(a)R^(a), C₁₋₄ alkyl    substituted with 0-3 R^(e), (CH₂)_(n)—C₃₋₆ carbocyclyl substituted    with 0-3 R^(e), and —(CH₂)_(n)-heterocyclyl substituted with 0-3    R^(e);-   R^(a), at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl    substituted with 0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted    with 0-5 R^(e); or R^(a) and R^(a) together with the nitrogen atom    to which they are both attached form a heterocyclic ring substituted    with 0-5 R^(e);-   R^(b), at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5    R^(e), C₂₋₆ alkynyl substituted with 0-5 R^(e),    —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e), and    —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e);-   R^(e), at each occurrence, is independently selected from F, Cl, Br,    CN, NO₂, ═O, CO₂H, C₁₋₆ alkyl (optionally substituted with F and    Cl), OH, OCH₃, OCF₃, —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)—C₄₋₆    heterocyclyl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, and    —(CH₂)_(n)OC₁₋₄alkyl; and-   n, at each occurrence, is independently selected from zero, 1, 2, 3,    and 4.

In another aspect, the present disclosure provides compounds of Formula(II), or stereoisomers, enantiomers, diastereoisomers, tautomers,pharmaceutically acceptable salts, prodrugs, or solvates thereof,wherein:

-   R¹, at each occurrence, is independently selected from H, F, Cl, OH,    CN, C₁₋₄ alkyl, and OC₁₋₄ alkyl;-   R² is independently selected from C₁₋₅ alkyl substituted with 0-3    R^(e); C₂₋₅ alkenyl, phenyl substituted with 0-3 R^(e), 5- to    6-membered heteroaryl substituted with 0-3 R^(e), C₃₋₆ cycloalkyl,    and CH₂O(CH₂)₁₋₃CH₃;-   R³ and R⁴ together with the nitrogen atom to which they are both    attached form a heterocyclic ring selected from

-   R⁵ is independently at each occurrence, selected from OH,

-   R⁸, at each occurrence, is independently selected from H, F, Cl, Br,    —OCH₃, —OCF₃, ═O, CN, CH₃, CF₃—(CH₂)_(n)-aryl, —(CH₂)_(n)—C₃₋₆    cycloalkyl substituted with 0-3 R^(e), and —(CH₂)_(n)-heterocyclyl    substituted with 0-3 R^(e);-   R^(8a), at each occurrence, is independently selected from H, CH₃,    aryl substituted with 0-3 R^(e), and heterocyclyl substituted with    0-3 R^(e);-   R^(a), at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl    substituted with 0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted    with 0-5 R^(e);-   R^(e), at each occurrence, is independently selected from F, Cl, Br,    CN, NO₂, ═O, CO₂H, C₁₋₆ alkyl (optionally substituted with F and    Cl), OH, OCH₃, OCF₃, —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)—C₄₋₆    heterocyclyl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, and    —(CH₂)_(n)OC₁₋₄alkyl; and-   n, at each occurrence, is independently selected from zero, 1, 2,    and 3.

In another aspect, the present disclosure provides compounds of Formula(III), or stereoisomers, enantiomers, diastereoisomers, tautomers,pharmaceutically acceptable salts, prodrugs, or solvates thereof,wherein:

-   ring B is independently selected from

-   R¹, at each occurrence, is independently selected from H, F, Cl, OH,    CN, C₁₋₄ alkyl, and OC₁₋₄ alkyl;-   R² is independently selected from C₁₋₅ alkyl substituted with 0-3    R^(e); C₂₋₅ alkenyl, phenyl substituted with 0-3 R^(e), 5- to    6-membered heteroaryl substituted with 0-3 R^(e), C₃₋₆ cycloalkyl,    and CH₂O(CH₂)₁₋₃CH₃;-   R⁵ is independently at each occurrence, selected from OH,

-   R⁸, at each occurrence, is independently selected from H, F, Cl, Br,    —OCH₃, —OCF₃, ═O, CN, CH₃, CF₃, —C(═O)NH₂, —(CH₂)_(n)-aryl    substituted with 0-3 R^(e), —(CH₂)_(n)—C₃₋₆ cycloalkyl substituted    with 0-3 R^(e), and —(CH₂)_(n)-heterocyclyl substituted with 0-3    R^(e);-   R^(8a), at each occurrence, is independently selected from H, CH₃,    aryl substituted with 0-3 R^(e), and heterocyclyl substituted with    0-3 R^(e);-   R^(a), at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl    substituted with 0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted    with 0-5 R^(e);-   R^(e), at each occurrence, is independently selected from F, Cl, Br,    CN, NO₂, ═O, CO₂H, C₁₋₆ alkyl (optionally substituted with F and    Cl), OH, OCH₃, OCF₃, —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)—C₄₋₆    heterocyclyl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, and    —(CH₂)_(n)OC₁₋₄alkyl; and-   n, at each occurrence, is independently selected from zero, 1, 2,    and 3.

In another aspect, the present disclosure provides compounds of Formula(II), or stereoisomers, enantiomers, diastereoisomers, tautomers,pharmaceutically acceptable salts, prodrugs, or solvates thereof,wherein:

-   R¹, at each occurrence, is independently selected from F, Cl, OH,    CH₂CH₃, —OCH₃, and OCD₃;-   R² is independently selected from C₁₋₅ alkyl substituted with 0-3    R^(e); C₂₋₅ alkenyl, phenyl substituted with 0-3 R^(e), 5- to    6-membered heteroaryl substituted with 0-3 R^(e), C₃₋₆ cycloalkyl,    and CH₂O(CH₂)₁₋₃CH₃;-   R³ and R⁴ together with the nitrogen atom to which they are both    attached form

-   R⁵, at each occurrence, is independently selected from OH, F, and    Cl;-   R^(5a), at each occurrence, is independently selected from

-   R⁸, at each occurrence, is independently selected from H, F, Cl, Br,    —OCH₃, —O(CH₂)₁₋₃OCH₃, —OCF₃, ═O, CN, CH₃, CF₃—(CH₂)_(n)-aryl,    —(CH₂)_(n)—C₃₋₆ cycloalkyl substituted with 0-3 R^(e), and    —(CH₂)_(n)-heterocyclyl substituted with 0-3 R^(e);-   R^(8a), at each occurrence, is independently selected from H, CH₃,    aryl substituted with 0-3 R^(e), and heterocyclyl substituted with    0-3 R^(e);-   R^(a), at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl    substituted with 0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted    with 0-5 R^(e);-   R^(b), at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5    R^(e), C₂₋₆ alkynyl substituted with 0-5 R^(e),    —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e), and    —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e);-   R^(e), at each occurrence, is independently selected from F, Cl, Br,    CN, NO₂, ═O, CO₂H, C₁₋₆ alkyl (optionally substituted with F and    Cl), OH, OCH₃, OCF₃, —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)—C₄₋₆    heterocyclyl, —(CH₂)_(n)-aryl, and —(CH₂)_(n)-heteroaryl; and-   n, at each occurrence, is independently selected from zero, 1, 2,    and 3.

In another aspect, the present disclosure provides compounds of Formula(I), or stereoisomers, enantiomers, diastereoisomers, tautomers,pharmaceutically acceptable salts, prodrugs, or solvates thereof,wherein:

-   R¹, at each occurrence, is independently selected from —CH₂OH,    —OCH₃, —OCH₃, —OCF₃, OCH₂Ph, —C(═O)NR^(a)R^(a), —NR^(a)R^(a), CH₃,    CH₂CH₃, CH(CH₃)₂, and cyclopropyl;-   R² is independently selected from C₁₋₄ alkyl substituted with 0-3    R^(e); C₂₋₄ alkenyl, phenyl substituted with 0-3 R^(e), 5- to    6-membered heteroaryl substituted with 0-3 R^(e), C₃₋₆ cycloalkyl,    and CH₂O(CH₂)₁₋₃CH₃;-   R³ is independently selected from H and C₁₋₄ alkyl:-   R⁴ is independently selected from —(CHR⁷)₁₋₄—R⁶, —(CH₂)₁₋₃OR⁶,    —(CH₂)₁₋₃NHR⁶, and —(CH₂)₀₋₃NHC(═O)R⁶;-   R⁶, at each occurrence, is independently selected from    —(CR⁷R⁷)_(n)-aryl, —(CR⁷R⁷)_(n)—C₃₋₆ cycloalkyl, and    —(CR⁷R⁷)_(n)-heteroaryl, each substituted with 0-3 R⁸;-   R⁷, at each occurrence, is independently selected from H, C₁₋₄    alkyl, and aryl;-   R⁸, at each occurrence, is independently selected from H, F, Cl,    —OR^(b), —NR^(a)R^(a), C₁₋₄ alkyl substituted with 0-3 R^(e), phenyl    substituted with 0-3 R^(e), and heterocyclyl substituted with 0-3    R^(e);-   R^(a), at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0-5 R^(e), —(CH₂)_(n)-phenyl substituted with    0-5 R^(e), and —(CH₂)_(n)-heteroaryl substituted with 0-5 R^(e);-   R^(b), at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl    substituted with 0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted    with 0-5 R^(e);-   R^(e), at each occurrence, is independently selected from F, Cl, Br,    CN, NO₂, ═O, CO₂H, C₁₋₆ alkyl (optionally substituted with F and    Cl), OH, OCH₃, OCF₃, —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)—C₄₋₆    heterocyclyl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl; and-   n is independently selected from zero, 1, 2, 3, and 4.

In another aspect, the present disclosure provides compounds of Formula(IV):

or stereoisomers, enantiomers, diastereoisomers, tautomers,pharmaceutically acceptable salts, prodrugs, or solvates thereof,wherein:

-   R¹, at each occurrence, is independently selected from F, Cl, OH,    C₁₋₂ alkyl, and OC₁₋₂ alkyl;-   R² is independently selected from —CH₂CH₂CH₂CH₃, —CH₂CH₂CH(CH₃)₂,    CH₂CH₂CH₂CF₃, —CH₂-cyclopropyl, —CH₂CH₂-cyclopropyl, cyclobutyl,    cyclopentyl, CH₂O(CH₂)₁₋₃CH₃, CH₂OCH(CH₃)₂, phenyl substituted with    0-2 R^(e), and 5- to 6-membered heteroaryl substituted with 0-2    R^(e);-   R⁵, at each occurrence, is independently selected from

-   R⁸, at each occurrence, is independently selected from F, Cl, Br,    —OCH₃, —OCF₃, ═O, CN, CH₃, CF₃, —C(═O)NH₂, —(CH₂)_(n)-aryl    substituted with 0-3 R^(e), —(CH₂)_(n)—C₃₋₆ cycloalkyl substituted    with 0-3 R^(e), and —(CH₂)_(n)-heterocyclyl substituted with 0-3    R^(e);-   R^(e), at each occurrence, is independently selected from F, Cl, Br,    CN, NO₂, ═O, CO₂H, C₁₋₆ alkyl (optionally substituted with F and    Cl), OH, OCH₃, OCF₃, —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)—C₄₋₆    heterocyclyl, —(CH₂)_(n)-aryl, and —(CH₂)_(n)-heteroaryl; and-   n is independently selected from zero, 1, 2, 3, and 4.

In another aspect, the present disclosure provides compounds of Formula(IV), or stereoisomers, enantiomers, diastereoisomers, tautomers,pharmaceutically acceptable salts, prodrugs, or solvates thereof,wherein:

-   R¹ is both CH₂CH₃ or both OCH₃;-   R² is independently selected from

-   R⁵ is independently at each occurrence, selected from

-   R⁸, at each occurrence, is independently selected from F, Cl, Br,    —OCH₃, —OCF₃, CN, CH₃, and CF₃; and-   R^(e), at each occurrence, is independently selected from F, Cl, Br,    C₁₋₃ alkyl, and cyclopropyl.

In another aspect, the present disclosure provides compounds of Formula(V):

or stereoisomers, enantiomers, diastereoisomers, tautomers,pharmaceutically acceptable salts, prodrugs, or solvates thereof,wherein:

-   ring B is independently selected from

-   R¹, at each occurrence, is independently selected from H, F, Cl, OH,    CN, and OC₁₋₄ alkyl;-   R² is independently selected from —CH₂CH₂CH₂CH₃, —CH₂CH₂CH(CH₃)₂,    CH₂CH₂CH₂CF₃, —CH₂-cyclopropyl, —CH₂CH₂-cyclopropyl, cyclobutyl,    cyclopentyl, CH₂O(CH₂)₁₋₃CH₃, and CH₂OCH(CH₃)₂, phenyl substituted    with 0-2 R^(e), and 5- to 6-membered heteroaryl substituted with 0-2    R^(e);-   R⁵, at each occurrence, is independently selected from

-   R⁸, at each occurrence, is independently selected from F, Cl, Br,    —OCH₃, —OCF₃, ═O, CN, CH₃, CF₃, —C(═O)NH₂, —(CH₂)_(n)-aryl    substituted with 0-3 R^(e), —(CH₂)_(n)—C₃₋₆ cycloalkyl substituted    with 0-3 R^(e), and —(CH₂)_(n)-heterocyclyl substituted with 0-3    R^(e);-   R^(e), at each occurrence, is independently selected from F, Cl, Br,    CN, NO₂, ═O, CO₂H, C₁₋₆ alkyl (optionally substituted with F and    Cl), OH, OCH₃, OCF₃, —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)—C₄₋₆    heterocyclyl, —(CH₂)_(n)-aryl, and —(CH₂)_(n)-heteroaryl;-   R^(e′) is independently selected from C₁₋₂ alkyl, —CH₂OC₁₋₂ alkyl,    and cyclopropyl; and-   n is independently selected from zero, 1, 2, 3, and 4.

In another aspect, the present disclosure provides compounds of Formula(VI):

or stereoisomers, enantiomers, diastereoisomers, tautomers,pharmaceutically acceptable salts, prodrugs, or solvates thereof,wherein:

-   R¹, at each occurrence, is independently selected from H, F, Cl, OH,    CN, and OC₁₋₄ alkyl;-   R² is independently selected from —CH₂CH₂CH₂CH₃, —CH₂CH₂CH(CH₃)₂,    CH₂CH₂CH₂CF₃, —CH₂-cyclopropyl, —CH₂CH₂-cyclopropyl, cyclobutyl,    cyclopentyl, CH₂O(CH₂)₁₋₃CH₃, and CH₂OCH(CH₃)₂,

-   R⁵, at each occurrence, is independently selected from

-   R⁸, at each occurrence, is independently selected from F, Cl, Br,    —OCH₃, —OCF₃, ═O, CN, CH₃, CF₃, —C(═O)NH₂, —(CH₂)_(n)-aryl    substituted with 0-3 R^(e), —(CH₂)_(n)—C₃₋₆ cycloalkyl substituted    with 0-3 R^(e), and —(CH₂)_(n)-heterocyclyl substituted with 0-3    R^(e);-   R^(e), at each occurrence, is independently selected from F, Cl, Br,    CN, NO₂, ═O, CO₂H, C₁₋₆ alkyl (optionally substituted with F and    Cl), OH, OCH₃, OCF₃, —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)—C₄₋₆    heterocyclyl, —(CH₂)_(n)-aryl, and —(CH₂)_(n)-heteroaryl;-   R^(e′) is independently selected from C₁₋₂ alkyl, —CH₂OC₁₋₂ alkyl,    and cyclopropyl; and-   n is independently selected from zero, 1, 2, 3, and 4.

In another aspect, the present disclosure provides compounds of Formula(VII):

or stereoisomers, enantiomers, diastereoisomers, tautomers,pharmaceutically acceptable salts, prodrugs, or solvates thereof,wherein:

-   R¹, at each occurrence, is independently selected from F, Cl, OH,    C₁₋₂ alkyl, and OC₁₋₂ alkyl;-   R² is independently selected from —CH₂CH₂CH₂CH₃, —CH₂CH₂CH(CH₃)₂,    CH₂CH₂CH₂CF₃, —CH₂-cyclopropyl, —CH₂CH₂-cyclopropyl, cyclobutyl,    cyclopentyl, CH₂O(CH₂)₁₋₃CH₃, CH₂OCH(CH₃)₂, phenyl substituted with    0-2 R^(e), and 5- to 6-membered heteroaryl substituted with 0-2    R^(e);-   R³ and R⁴ together with the nitrogen atom to which they are both    attached form a heterocyclic ring selected from

-   R⁵ is independently at each occurrence, selected from

-   R^(5a) is

-   R⁸, at each occurrence, is independently selected from F, Cl, Br,    —OCH₃, —OCF₃, ═O, CN, CH₃, CF₃, —C(═O)NH₂, —(CH₂)_(n)-aryl    substituted with 0-3 R^(e), —(CH₂)_(n)—C₃₋₆ cycloalkyl substituted    with 0-3 R^(e), and —(CH₂)_(n)-heterocyclyl substituted with 0-3    R^(e);-   R^(e), at each occurrence, is independently selected from F, Cl, Br,    CN, NO₂, ═O, CO₂H, C₁₋₆ alkyl (optionally substituted with F and    Cl), OH, OCH₃, OCF₃, —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)—C₄₋₆    heterocyclyl, —(CH₂)_(n)-aryl, and —(CH₂)_(n)-heteroaryl; and-   n is independently selected from zero, 1, 2, 3, and 4.

In another aspect, the present disclosure provides compounds of Formula(VIII):

or stereoisomers, enantiomers, diastereoisomers, tautomers,pharmaceutically acceptable salts, prodrugs, or solvates thereof,wherein:

-   R¹ is both C₁₋₂ alkyl or both —OC₁₋₂ alkyl;-   R² is independently selected from —CH₂CH₂CH₂CH₃, —CH₂CH₂CH(CH₃)₂,    CH₂CH₂CH₂CF₃, —CH₂-cyclopropyl, —CH₂CH₂-cyclopropyl, cyclobutyl,    cyclopentyl, CH₂O(CH₂)₁₋₃CH₃, CH₂OCH(CH₃)₂, phenyl substituted with    0-2 R^(e), and 5- to 6-membered heteroaryl substituted with 0-2    R^(e);-   R⁵, at each occurrence, is independently selected from

-   R⁸, at each occurrence, is independently selected from F, Cl, Br,    —OCH₃, —OCF₃, ═O, CN, CH₃, CF₃, —C(═O)NH₂, —(CH₂)_(n)-aryl    substituted with 0-3 R^(e), —(CH₂)_(n)—C₃₋₆ cycloalkyl substituted    with 0-3 R^(e), and —(CH₂)_(n)-heterocyclyl substituted with 0-3    R^(e);-   R^(e), at each occurrence, is independently selected from F, Cl, Br,    CN, NO₂, ═O, CO₂H, C₁₋₆ alkyl (optionally substituted with F and    Cl), OH, OCH₃, OCF₃, —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)—C₄₋₆    heterocyclyl, —(CH₂)_(n)-aryl, and —(CH₂)_(n)-heteroaryl; and-   n is independently selected from zero, 1, 2, 3, and 4.

In another aspect, the present disclosure provides compounds of Formula(IX):

or stereoisomers, enantiomers, diastereoisomers, tautomers,pharmaceutically acceptable salts, prodrugs, or solvates thereof,wherein:ring B is

-   R¹ is independently selected from H, F, Cl, OH, C₁₋₃ alkyl, and    OC₁₋₃ alkyl;-   R^(1a) is independently selected from F and Cl;-   R² is independently selected from —CH₂CH₂CH₂CH₃, —CH₂CH₂CH(CH₃)₂,    CH₂CH₂CH₂CF₃, —CH₂-cyclopropyl, —CH₂CH₂-cyclopropyl, cyclobutyl,    cyclopentyl, CH₂O(CH₂)₁₋₃CH₃, and CH₂OCH(CH₃)₂,

-   R³ and R⁴ together with the nitrogen atom to which they are both    attached form

-   R⁵, at each occurrence, is independently selected from

-   R⁸, at each occurrence, is independently selected from F, Cl, Br,    —OCH₃, —OCF₃, CN, CH₃, and CF₃; and-   R^(e), at each occurrence, is independently selected from F, Cl, Br,    and C₁₋₃ alkyl.

In another embodiment of Formula (IX), ring B is

R¹ is independently selected from H, F, Cl, OH, C₁₋₃ alkyl, and OC₁₋₃alkyl, and other variables are as defined in Formula (IX).

In another embodiment of Formula (IX), ring B is

R¹ is independently selected from H, F, Cl, OH, C₁₋₃ alkyl, and OC₁₋₃alkyl, and other variables are as defined in Formula (IX).

In another embodiment of Formula (IX), ring B is

R¹ is both CH₂CH₃ or both OCH₃, R³ and R⁴ together with the nitrogenatom to which they are both attached form

and other variables are as defined in Formula (IX).

In another embodiment of Formula (IX), ring B is

R¹ is both CH₂CH₃ or both OCH₃, R³ and R⁴ together with the nitrogenatom to which they are both attached form

R^(5a) is

and other variables are as defined in Formula (IX).

In another aspect, the present disclosure provides compounds of Formula(X):

or stereoisomers, enantiomers, diastereoisomers, tautomers,pharmaceutically acceptable salts, prodrugs, or solvates thereof,wherein:

-   ring B is independently selected from

-   R¹, at each occurrence, is independently selected from H, F, Cl, OH,    CN, and OC₁₋₄ alkyl;-   R² is independently selected from —CH₂CH₂CH₂CH₃, —CH₂CH₂CH(CH₃)₂,    CH₂CH₂CH₂CF₃, —CH₂-cyclopropyl, —CH₂CH₂-cyclopropyl, cyclobutyl,    cyclopentyl, CH₂O(CH₂)₁₋₃CH₃, and CH₂OCH(CH₃)₂,

-   R³ and R⁴ together with the nitrogen atom to which they are both    attached form

-   R⁵, at each occurrence, is independently selected from

-   R⁸, at each occurrence, is independently selected from F, Cl, Br,    —OCH₃, —OCF₃, ═O, CN, CH₃, CF₃, —C(═O)NH₂, —(CH₂)_(n)-aryl    substituted with 0-3 R^(e), —(CH₂)_(n)—C₃₋₆ cycloalkyl substituted    with 0-3 R^(e), and —(CH₂)_(n)-heterocyclyl substituted with 0-3    R^(e);-   R^(e), at each occurrence, is independently selected from F, Cl, Br,    CN, NO₂, ═O, CO₂H, C₁₋₆ alkyl (optionally substituted with F and    Cl), OH, OCH₃, OCF₃, —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)—C₄₋₆    heterocyclyl, —(CH₂)_(n)-aryl, and —(CH₂)_(n)-heteroaryl;-   R^(e′) is independently selected from C₁₋₂ alkyl, —CH₂OC₁₋₂ alkyl,    and cyclopropyl; and-   n is independently selected from zero, 1, 2, 3, and 4.

In another embodiment of Formula (X), ring B is

R¹ is independently selected from H, F, Cl, and CN, R³ and R⁴ togetherwith the nitrogen atom to which they are both attached form

and other variables are as defined in Formula (X).

In another embodiment of Formula (X), ring B is

R¹ is independently selected from H, F, Cl, and CN, R³ and R⁴ togetherwith the nitrogen atom to which they are both attached form

R^(5a) is

and other variables are as defined in Formula (X).

In another aspect, the present invention provides a compound selectedfrom

-   2-Butyl-5-(3-(5-chloropyridin-2-yl)pyrrolidine-1-carbonyl)-1-(2,6-dimethoxyphenyl)-6-hydroxypyrimidin-4(1H)-one    (1),-   (R)-2-Butyl-1-(2,6-dicyclopropylphenyl)-6-hydroxy-5-(3-phenylpyrrolidine-1-carbonyl)pyrimidin-4(1H)-one    (2),-   1-(2,6-Dimethoxyphenyl)-2-(ethoxymethyl)-6-hydroxy-5-(3-(pyridin-2-yl)pyrrolidine-1-carbonyl)pyrimidin-4(1H)-one    (3),-   (S)-2-(2-Cyclopropylethyl)-1-(2,6-dimethoxyphenyl)-6-hydroxy-5-(3-phenylpyrrolidine-1-carbonyl)pyrimidin-4(1H)-one    (4),-   (R)-1-(2,6-Bis(methoxy-d₃)phenyl)-2-butyl-6-hydroxy-5-(3-phenylpyrrolidine-1-carbonyl)pyrimidin-4(1H)-one    (5),-   2-Butyl-6-hydroxy-3-((S)-1-phenylpropyl)-5-((R)-3-phenylpyrrolidine-1-carbonyl)pyrimidin-4(3H)-one    (6),-   1-(2,6-dimethoxyphenyl)-6-hydroxy-5-(3-(2-methoxyphenyl)pyrrolidine-1-carbonyl)-2-(5-methylpyridin-3-yl)pyrimidin-4(1H)-one    (7),-   (R)-2-(but-3-en-1-yl)-6-hydroxy-3-(2-methoxy-6-methylphenyl)-5-(3-phenylpyrrolidine-1-carbonyl)pyrimidin-4(3H)-one,    diastereomer 1 and diastereomer (8),-   1-(2,6-dimethoxyphenyl)-6-hydroxy-2-(isopropoxymethyl)-5-(3-(p-tolyl)azetidine-1-carbonyl)pyrimidin-4(1H)-one    (9),-   2-(cyclopropoxymethyl)-1-(2,6-dimethoxyphenyl)-5-(3-(2-fluorophenyl)pyrrolidine-1-carbonyl)-6-hydroxypyrimidin-4(1H)-one    (10),-   (R)-2-(cyclopropoxymethyl)-3-(2,6-dimethoxyphenyl)-6-hydroxy-5-(3-phenylpyrrolidine-1-carbonyl)pyrimidin-4(3H)-one    (11),-   (R)-1-(2,6-dimethoxyphenyl)-6-hydroxy-2-(isopropoxymethyl)-5-(3-phenylpyrrolidine-1-carbonyl)pyrimidin-4(1H)-one    (12),-   2-(cyclopropoxymethyl)-1-(2,6-dimethoxyphenyl)-5-(3-(2-fluorophenyl)pyrrolidine-1-carbonyl)-6-hydroxypyrimidin-4(1H)-one    (13),-   (R)-1-(2,6-dimethoxyphenyl)-6-hydroxy-2-isopentyl-5-(3-phenylpyrrolidine-1-carbonyl)pyrimidin-4(1H)-one    (14),-   2-(cyclopropoxymethyl)-1-(2,6-dimethoxyphenyl)-5-(3-(3-fluorophenyl)pyrrolidine-1-carbonyl)-6-hydroxypyrimidin-4(1H)-one    (15),-   (S)-2-(but-3-en-1-yl)-3-(2,6-dimethoxyphenyl)-6-hydroxy-5-(3-phenylpyrrolidine-1-carbonyl)pyrimidin-4(3H)-one    (16),-   (R)-3-(2,6-diethylphenyl)-6-hydroxy-2-(isopropoxymethyl)-5-(3-phenylpyrrolidine-1-carbonyl)pyrimidin-4(3H)-one    (17),-   1-(2,6-diethylphenyl)-6-hydroxy-2-(isopropoxymethyl)-5-(3-(pyridin-2-yl)pyrrolidine-1-carbonyl)pyrimidin-4(1H)-one    (18),-   2-(cyclopropoxymethyl)-1-(2,6-dimethoxyphenyl)-6-hydroxy-5-(3-(o-tolyl)pyrrolidine-1-carbonyl)pyrimidin-4(1H)-one    (19),-   (R)-2-(cyclobutoxymethyl)-3-(2,6-dimethoxyphenyl)-6-hydroxy-5-(3-phenylpyrrolidine-1-carbonyl)pyrimidin-4(3H)-one    (20),-   5-(3-(4-chlorophenyl)pyrrolidine-1-carbonyl)-2-(cyclopropoxymethyl)-1-(2,6-dimethoxyphenyl)-6-hydroxypyrimidin-4(1H)-one    (21),-   5-(3-(2-chlorophenyl)pyrrolidine-1-carbonyl)-2-(cyclopropoxymethyl)-1-(2,6-dimethoxyphenyl)-6-hydroxypyrimidin-4(1H)-one    (22),-   (R)-1-(2,6-dimethoxyphenyl)-2-(ethoxymethyl)-6-hydroxy-5-(3-phenylpyrrolidine-1-carbonyl)pyrimidin-4(1H)-one    (23),-   (S)-1-(2,6-dimethoxyphenyl)-6-hydroxy-2-isopentyl-5-(3-phenylpyrrolidine-1-carbonyl)pyrimidin-4(1H)-one    (24),-   1-(2,6-diethylphenyl)-5-(3-(2-fluorophenyl)pyrrolidine-1-carbonyl)-6-hydroxy-2-(isopropoxymethyl)pyrimidin-4(1H)-one    (25),-   5-(3-(3-chlorophenyl)pyrrolidine-1-carbonyl)-1-(2,6-dimethoxyphenyl)-2-(ethoxymethyl)-6-hydroxypyrimidin-4(1H)-one    (26),-   (R)-2-(but-3-en-1-yl)-3-(2,6-dimethoxyphenyl)-6-hydroxy-5-(3-phenylpyrrolidine-1-carbonyl)pyrimidin-4(3H)-one    (27),-   5-(3-(3-chlorophenyl)pyrrolidine-1-carbonyl)-2-(cyclopropylmethyl)-1-(2,6-dimethoxyphenyl)-6-hydroxypyrimidin-4(1H)-one    (28),-   (S)-1-(2,6-dimethoxyphenyl)-2-(ethoxymethyl)-6-hydroxy-5-(3-phenylpyrrolidine-1-carbonyl)pyrimidin-4(1H)-one    (29),-   (R)-2-cyclopentyl-3-(2,6-dimethoxyphenyl)-6-hydroxy-5-(3-phenylpyrrolidine-1-carbonyl)pyrimidin-4(3H)-one    (30),-   (S)-2-(cyclopropylmethyl)-3-(2,6-dimethoxyphenyl)-6-hydroxy-5-(3-phenylpyrrolidine-1-carbonyl)pyrimidin-4(3H)-one    (31),-   (R)-2-(cyclopropylmethyl)-3-(2,6-dimethoxyphenyl)-6-hydroxy-5-(3-phenylpyrrolidine-1-carbonyl)pyrimidin-4(3H)-one    (32),-   (S)-1-(2,6-dimethoxyphenyl)-6-hydroxy-5-(3-phenylpyrrolidine-1-carbonyl)-2-(4,4,4-trifluorobutyl)pyrimidin-4(1H)-one    (33),-   (S)-2-cyclopentyl-3-(2,6-dimethoxyphenyl)-6-hydroxy-5-(3-phenylpyrrolidine-1-carbonyl)pyrimidin-4(3H)-one    (34),-   (R)-2-(but-3-en-1-yl)-6-hydroxy-3-(2-methoxy-6-methylphenyl)-5-(3-phenylpyrrolidine-1-carbonyl)pyrimidin-4(3H)-one    (35),-   (S)-1-(2,6-dimethoxyphenyl)-6-hydroxy-5-(3-phenylpyrrolidine-1-carbonyl)-2-(4,4,4-trifluorobutyl)pyrimidin-4(1H)-one    (36),-   (R)-1-(2,6-dimethoxyphenyl)-6-hydroxy-5-(3-phenylpyrrolidine-1-carbonyl)-2-(4,4,4-trifluorobutyl)pyrimidin-4(1H)-one    (40),-   2-butyl-5-(3-(5-chloropyridin-2-yl)pyrrolidine-1-carbonyl)-1-(2,6-dimethoxyphenyl)-6-hydroxypyrimidin-4(1H)-one    (41),-   2-[(tert-butoxy)methyl]-5-[3-(2-chlorophenyl)pyrrolidine-1-carbonyl]-1-(2,6-dimethoxyphenyl)-6-hydroxy-1,4-dihydropyrimidin-4-one    (42),-   2-butyl-5-[3-(2-chlorophenyl)pyrrolidine-1-carbonyl]-1-(2,6-dimethoxyphenyl)-6-hydroxy-1,4-dihydropyrimidin-4-one    (43),-   2-[(tert-butoxy)methyl]-1-(2,6-dimethoxyphenyl)-5-[3-(4-fluorophenyl)pyrrolidine-1-carbonyl]-6-hydroxy-1,4-dihydropyrimidin-4-one    (44),-   2-butyl-5-[3-(4-chlorophenyl)pyrrolidine-1-carbonyl]-1-(2,6-dimethoxyphenyl)-6-hydroxy-1,4-dihydropyrimidin-4-one    (45),-   2-butyl-5-[3-(4-chlorophenyl)pyrrolidine-1-carbonyl]-1-(2,6-dimethoxyphenyl)-6-hydroxy-1,4-dihydropyrimidin-4-one    (46),-   2-butyl-1-(2,6-dimethoxyphenyl)-6-hydroxy-5-[3-(pyridin-4-yl)pyrrolidine-1-carbonyl]-1,4-dihydropyrimidin-4-one    (47),-   2-butyl-1-(2,6-dimethoxyphenyl)-6-hydroxy-5-[3-(pyridin-4-yl)pyrrolidine-1-carbonyl]-1,4-dihydropyrimidin-4-one    (48),-   1-(2,6-dimethoxyphenyl)-2-(ethoxymethyl)-5-[3-(2-fluorophenyl)pyrrolidine-1-carbonyl]-6-hydroxy-1,4-dihydropyrimidin-4-one    (49),-   2-[(tert-butoxy)methyl]-1-(2,6-dimethoxyphenyl)-5-[3-(2-fluorophenyl)pyrrolidine-1-carbonyl]-6-hydroxy-1,4-dihydropyrimidin-4-one    (50),-   2-[(tert-butoxy)methyl]-1-(2,6-dimethoxyphenyl)-6-hydroxy-5-[(3R)-3-phenylpyrrolidine-1-carbonyl]-1,4-dihydropyrimidin-4-one    (51),-   2-butyl-1-(2,6-dimethoxyphenyl)-5-[3-(2-fluorophenyl)pyrrolidine-1-carbonyl]-6-hydroxy-1,4-dihydropyrimidin-4-one    (52),-   2-butyl-1-(2,6-dimethoxyphenyl)-5-[3-(2-fluorophenyl)pyrrolidine-1-carbonyl]-6-hydroxy-1,4-dihydropyrimidin-4-one    (53),-   1-(2,6-dimethoxyphenyl)-2-(ethoxymethyl)-6-hydroxy-5-[3-(pyridin-2-yl)pyrrolidine-1-carbonyl]-1,4-dihydropyrimidin-4-one    (54),-   1-(2,6-dimethoxyphenyl)-2-(ethoxymethyl)-6-hydroxy-5-[3-(pyridin-2-yl)pyrrolidine-1-carbonyl]-1,4-dihydropyrimidin-4-one    (55),-   2-butyl-1-(2,6-dimethoxyphenyl)-5-(5-fluoro-2,3-dihydro-1H-isoindole-2-carbonyl)-6-hydroxy-1,4-dihydropyrimidin-4-one    (56),-   1-(2,6-dimethoxyphenyl)-2-(ethoxymethyl)-5-[3-(4-fluorophenyl)pyrrolidine-1-carbonyl]-6-hydroxy-1,4-dihydropyrimidin-4-one    (57),-   benzyl    N-[(3S)-1-[2-butyl-1-(2,6-dimethoxyphenyl)-6-hydroxy-4-oxo-1,4-dihydropyrimidine-5-carbonyl]pyrrolidin-3-yl]carbamate    (58),-   5-[(3R)-3-(benzyloxy)pyrrolidine-1-carbonyl]-2-butyl-1-(2,6-dimethoxyphenyl)-6-hydroxy-1,4-dihydropyrimidin-4-one    (59),-   2-butyl-1-(2,6-dimethoxyphenyl)-6-hydroxy-5-{1H,2H,3H-pyrrolo[3,4-c]pyridine-2-carbonyl}-1,4-dihydropyrimidin-4-one    (60),-   2-butyl-1-(2,6-dimethoxyphenyl)-6-hydroxy-5-{5H,6H,7H-pyrrolo[3,4-b]pyridine-6-carbonyl}-1,4-dihydropyrimidin-4-one    (61),-   benzyl    N-[(3R)-1-[2-butyl-1-(2,6-dimethoxyphenyl)-6-hydroxy-4-oxo-1,4-dihydropyrimidine-5-carbonyl]pyrrolidin-3-yl]carbamate    (62),-   5-[(3S)-3-(benzyloxy)pyrrolidine-1-carbonyl]-2-butyl-1-(2,6-dimethoxyphenyl)-6-hydroxy-1,4-dihydropyrimidin-4-one    (63),-   2-butyl-1-(2,6-dimethoxyphenyl)-6-hydroxy-5-[(3S)-3-[(pyridin-2-yl)methoxy]pyrrolidine-1-carbonyl]-1,4-dihydropyrimidin-4-one    (64),-   2-[2-butyl-1-(2,6-dimethoxyphenyl)-6-hydroxy-4-oxo-1,4-dihydropyrimidine-5-carbonyl]-2,3-dihydro-1H-isoindole-5-carbonitrile    (65),-   2-butyl-5-(2,3-dihydro-1H-isoindole-2-carbonyl)-1-(2,6-dimethoxyphenyl)-6-hydroxy-1,4-dihydropyrimidin-4-one    (66),-   2-butyl-1-(2,6-dimethoxyphenyl)-5-{3-[(4-fluorophenyl)methyl]pyrrolidine-1-carbonyl}-6-hydroxy-1,4-dihydropyrimidin-4-one    (67),-   2-butyl-1-(2,6-dimethoxyphenyl)-6-hydroxy-5-[3-(pyridin-2-yl)pyrrolidine-1-carbonyl]-1,4-dihydropyrimidin-4-one    (68),-   2-butyl-1-(2,6-dimethoxyphenyl)-5-{4-[(3-fluorophenyl)methyl]piperazine-1-carbonyl}-6-hydroxy-1,4-dihydropyrimidin-4-one    (69),-   2-butyl-1-(2,6-dimethoxyphenyl)-6-hydroxy-5-[3-(pyridin-2-yl)pyrrolidine-1-carbonyl]-1,4-dihydropyrimidin-4-one    (70),-   2-butyl-1-(2,6-dimethoxyphenyl)-6-hydroxy-5-[4-(pyridin-4-yl)piperidine-1-carbonyl]-1,4-dihydropyrimidin-4-one    (71),-   2-butyl-1-(2,6-dimethoxyphenyl)-6-hydroxy-5-(4-phenylpiperidine-1-carbonyl)-1,4-dihydropyrimidin-4-one    (72),-   5-(3-benzylpyrrolidine-1-carbonyl)-2-butyl-1-(2,6-dimethoxyphenyl)-6-hydroxy-1,4-dihydropyrimidin-4-one    (73),-   2-butyl-1-(2,6-dimethoxyphenyl)-5-[4-(4-fluorophenyl)piperidine-1-carbonyl]-6-hydroxy-1,4-dihydropyrimidin-4-one    (74),-   2-butyl-1-(2,6-dimethoxyphenyl)-6-hydroxy-5-[3-(pyridin-3-yl)pyrrolidine-1-carbonyl]-1,4-dihydropyrimidin-4-one    (75),-   2-butyl-1-(2,6-dimethoxyphenyl)-6-hydroxy-5-[3-(pyridin-3-yl)pyrrolidine-1-carbonyl]-1,4-dihydropyrimidin-4-one    (76),-   2-butyl-1-(2,6-dimethoxyphenyl)-5-[3-(4-fluorophenyl)pyrrolidine-1-carbonyl]-6-hydroxy-1,4-dihydropyrimidin-4-one    (77),-   2-butyl-1-(2,6-dimethoxyphenyl)-5-[3-(3-fluorophenyl)pyrrolidine-1-carbonyl]-6-hydroxy-1,4-dihydropyrimidin-4-one    (78),-   2-butyl-1-(2,6-dimethoxyphenyl)-5-[3-(4-fluorophenyl)pyrrolidine-1-carbonyl]-6-hydroxy-1,4-dihydropyrimidin-4-one    (79),-   2-butyl-1-(2,6-dimethoxyphenyl)-5-[3-(3-fluorophenyl)pyrrolidine-1-carbonyl]-6-hydroxy-1,4-dihydropyrimidin-4-one    (80),-   1-(2,6-dimethoxyphenyl)-2-(ethoxymethyl)-5-[3-(4-fluorophenyl)pyrrolidine-1-carbonyl]-6-hydroxy-1,4-dihydropyrimidin-4-one    (81),-   1-(2,6-dimethoxyphenyl)-2-(ethoxymethyl)-6-hydroxy-5-[3-(pyridin-3-yl)pyrrolidine-1-carbonyl]-1,4-dihydropyrimidin-4-one    (82),-   1-(2,6-dimethoxyphenyl)-2-(ethoxymethyl)-5-[3-(3-fluorophenyl)pyrrolidine-1-carbonyl]-6-hydroxy-1,4-dihydropyrimidin-4-one    (83),-   1-(2,6-dimethoxyphenyl)-2-(ethoxymethyl)-5-[3-(3-fluorophenyl)pyrrolidine-1-carbonyl]-6-hydroxy-1,4-dihydropyrimidin-4-one    (84),-   1-(2,6-dimethoxyphenyl)-2-(ethoxymethyl)-6-hydroxy-5-[3-(pyridin-3-yl)pyrrolidine-1-carbonyl]-1,4-dihydropyrimidin-4-one    (85),-   2-butyl-3-(2,6-diethylphenyl)-6-hydroxy-5-[(3S)-3-phenylpyrrolidine-1-carbonyl]-3,4-dihydropyrimidin-4-one    (86),-   2-butyl-3-(2,6-dimethoxyphenyl)-5-[3-(4-fluorophenyl)pyrrolidine-1-carbonyl]-6-hydroxy-3,4-dihydropyrimidin-4-one    (87),-   2-butyl-5-[3-(3-chlorophenyl)azetidine-1-carbonyl]-3-(2,6-dimethoxyphenyl)-6-hydroxy-3,4-dihydropyrimidin-4-one    (88),-   2-butyl-3-(2,6-diethylphenyl)-5-[3-(4-fluorophenyl)pyrrolidine-1-carbonyl]-6-hydroxy-3,4-dihydropyrimidin-4-one    (89),-   2-butyl-3-(2,6-diethylphenyl)-6-hydroxy-5-[(3R)-3-phenylpyrrolidine-1-carbonyl]-3,4-dihydropyrimidin-4-one    (90),-   2-butyl-3-(2,6-dimethoxyphenyl)-6-hydroxy-5-[(3S)-3-phenylpyrrolidine-1-carbonyl]-3,4-dihydropyrimidin-4-one    (91),-   5-[3-(2-chlorophenyl)pyrrolidine-1-carbonyl]-1-(2,6-dimethoxyphenyl)-6-hydroxy-2-[(propan-2-yloxy)methyl]-1,4-dihydropyrimidin-4-one    (92),-   1-(2,6-dimethoxyphenyl)-5-[3-(2-fluorophenyl)pyrrolidine-1-carbonyl]-6-hydroxy-2-[(propan-2-yloxy)methyl]-1,4-dihydropyrimidin-4-one    (93),-   1-(2,6-dimethoxyphenyl)-5-[3-(4-fluorophenyl)pyrrolidine-1-carbonyl]-6-hydroxy-2-[(propan-2-yloxy)methyl]-1,4-dihydropyrimidin-4-one    (94),-   1-(2,6-dimethoxyphenyl)-5-[3-(3-fluorophenyl)pyrrolidine-1-carbonyl]-6-hydroxy-2-[(propan-2-yloxy)methyl]-1,4-dihydropyrimidin-4-one    (95),-   2-(2-cyclopropylethyl)-1-(2,6-dimethoxyphenyl)-6-hydroxy-5-[(3R)-3-phenylpyrrolidine-1-carbonyl]-1,4-dihydropyrimidin-4-one    (96),-   1-(2,6-dimethoxyphenyl)-5-[3-(3-fluorophenyl)pyrrolidine-1-carbonyl]-6-hydroxy-2-[(propan-2-yloxy)methyl]-1,4-dihydropyrimidin-4-one    (97),-   1-(2,6-dimethoxyphenyl)-6-hydroxy-5-[3-(2-methylphenyl)pyrrolidine-1-carbonyl]-2-[(propan-2-yloxy)methyl]-1,4-dihydropyrimidin-4-one    (98),-   1-(2,6-dimethoxyphenyl)-6-hydroxy-2-[(propan-2-yloxy)methyl]-5-{3-[2-(trifluoromethyl)phenyl]pyrrolidine-1-carbonyl}-1,4-dihydropyrimidin-4-one    (99),-   2-(cyclopropoxymethyl)-1-(2,6-dimethoxyphenyl)-5-[3-(4-fluorophenyl)pyrrolidine-1-carbonyl]-6-hydroxy-1,4-dihydropyrimidin-4-one    (100),-   1-(2,6-dimethoxyphenyl)-6-hydroxy-2-[(propan-2-yloxy)methyl]-5-{3-[2-(trifluoromethyl)phenyl]pyrrolidine-1-carbonyl}-1,4-dihydropyrimidin-4-one    (101)-   1-(2,6-dimethoxyphenyl)-5-[3-(4-fluorophenyl)pyrrolidine-1-carbonyl]-6-hydroxy-2-[(propan-2-yloxy)methyl]-1,4-dihydropyrimidin-4-one    (102),-   2-(cyclopropoxymethyl)-1-(2,6-dimethoxyphenyl)-5-[3-(4-fluorophenyl)pyrrolidine-1-carbonyl]-6-hydroxy-1,4-dihydropyrimidin-4-one    (103),-   1-[2,6-bis(²H₃)methoxyphenyl]-2-butyl-6-hydroxy-5-[(3S)-3-phenylpyrrolidine-1-carbonyl]-1,4-dihydropyrimidin-4-one    (104),-   1-(2,6-dimethoxyphenyl)-6-hydroxy-5-[3-(2-methylphenyl)pyrrolidine-1-carbonyl]-2-[(propan-2-yloxy)methyl]-1,4-dihydropyrimidin-4-one    (105),-   1-[2,6-bis(²H₃)methoxyphenyl]-2-(ethoxymethyl)-6-hydroxy-5-[(3R)-3-phenylpyrrolidine-1-carbonyl]-1,4-dihydropyrimidin-4-one    (106),-   4-{1-[1-(2,6-dimethoxyphenyl)-6-hydroxy-4-oxo-2-[(propan-2-yloxy)methyl]-1,4-dihydropyrimidine-5-carbonyl]pyrrolidin-3-yl}benzonitrile    (107),-   4-{1-[1-(2,6-dimethoxyphenyl)-6-hydroxy-4-oxo-2-[(propan-2-yloxy)methyl]-1,4-dihydropyrimidine-5-carbonyl]pyrrolidin-3-yl}benzonitrile    (108),-   1-[2,6-bis(²H₃)methoxyphenyl]-2-(ethoxymethyl)-6-hydroxy-5-[(3S)-3-phenylpyrrolidine-1-carbonyl]-1,4-dihydropyrimidin-4-one    (109),-   1-(2,6-dimethoxyphenyl)-6-hydroxy-5-(3-phenylazetidine-1-carbonyl)-2-[(propan-2-yloxy)methyl]-1,4-dihydropyrimidin-4-one    (110),-   1-(2,6-dimethoxyphenyl)-6-hydroxy-5-[3-(4-methylphenyl)azetidine-1-carbonyl]-2-[(propan-2-yloxy)methyl]-1,4-dihydropyrimidin-4-one    (111),-   2-butyl-3-(4,6-dimethoxypyrimidin-5-yl)-6-hydroxy-5-[(3S)-3-phenylpyrrolidine-1-carbonyl]-3,4-dihydropyrimidin-4-one    (112),-   2-butyl-3-(4,6-dimethoxypyrimidin-5-yl)-6-hydroxy-5-[(3R)-3-phenylpyrrolidine-1-carbonyl]-3,4-dihydropyrimidin-4-one    (113),-   2-butyl-5-[3-(2-fluorophenyl)pyrrolidine-1-carbonyl]-6-hydroxy-3-[(1S)-1-phenylpropyl]-3,4-dihydropyrimidin-4-one    (114),-   2-butyl-5-[3-(3-fluorophenyl)pyrrolidine-1-carbonyl]-6-hydroxy-3-[(1S)-1-phenylpropyl]-3,4-dihydropyrimidin-4-one    (115),-   2-butyl-6-hydroxy-3-[(1R)-2-methoxy-1-phenylethyl]-5-[(3R)-3-phenylpyrrolidine-1-carbonyl]-3,4-dihydropyrimidin-4-one    (116),-   2-butyl-6-hydroxy-3-[(1R)-1-phenylethyl]-5-[(3R)-3-phenylpyrrolidine-1-carbonyl]-3,4-dihydropyrimidin-4-one    (117),-   2-butyl-5-[3-(2-fluorophenyl)pyrrolidine-1-carbonyl]-6-hydroxy-3-[(1S)-1-phenylpropyl]-3,4-dihydropyrimidin-4-one    (118),-   2-butyl-5-[3-(3-fluorophenyl)pyrrolidine-1-carbonyl]-6-hydroxy-3-[(1S)-1-phenylpropyl]-3,4-dihydropyrimidin-4-one    (119),-   2-butyl-6-hydroxy-3-[(1S)-1-(3-methoxyphenyl)ethyl]-5-[(3S)-3-phenylpyrrolidine-1-carbonyl]-3,4-dihydropyrimidin-4-one    (120),-   2-butyl-6-hydroxy-3-[(1S)-1-phenylpropyl]-5-[(3S)-3-phenylpyrrolidine-1-carbonyl]-3,4-dihydropyrimidin-4-one    (121),-   2-butyl-6-hydroxy-3-[(1R)-1-(2-methoxyphenyl)ethyl]-5-[(3R)-3-phenylpyrrolidine-1-carbonyl]-3,4-dihydropyrimidin-4-one    (122),-   2-butyl-6-hydroxy-3-(1-phenylethyl)-5-[(3R)-3-phenylpyrrolidine-1-carbonyl]-3,4-dihydropyrimidin-4-one    (123),-   2-butyl-6-hydroxy-3-[(1R)-1-phenylpropyl]-5-[(3R)-3-phenylpyrrolidine-1-carbonyl]-3,4-dihydropyrimidin-4-one    (124),-   2-butyl-6-hydroxy-3-[(1S)-1-phenylethyl]-5-[(3S)-3-phenylpyrrolidine-1-carbonyl]-3,4-dihydropyrimidin-4-one    (125),-   2-butyl-3-[(1S)-1-cyclopropylethyl]-6-hydroxy-5-[(3R)-3-phenylpyrrolidine-1-carbonyl]-3,4-dihydropyrimidin-4-one    (126),-   2-butyl-6-hydroxy-3-[(1R)-2-methoxy-1-phenylethyl]-5-[(3S)-3-phenylpyrrolidine-1-carbonyl]-3,4-dihydropyrimidin-4-one    (127),-   2-butyl-6-hydroxy-3-[(1R)-1-phenylpropyl]-5-[(3S)-3-phenylpyrrolidine-1-carbonyl]-3,4-dihydropyrimidin-4-one    (128),-   2-butyl-6-hydroxy-3-(2-methyl-1-phenylpropyl)-5-[(3S)-3-phenylpyrrolidine-1-carbonyl]-3,4-dihydropyrimidin-4-one    (129),-   2-butyl-6-hydroxy-3-(2-methyl-1-phenylpropyl)-5-[(3R)-3-phenylpyrrolidine-1-carbonyl]-3,4-dihydropyrimidin-4-one    (130),-   2-butyl-3-[(1S)-1-cyclopropylethyl]-6-hydroxy-5-[(3S)-3-phenylpyrrolidine-1-carbonyl]-3,4-dihydropyrimidin-4-one    (131),-   2-butyl-6-hydroxy-3-[(1R)-1-phenylethyl]-5-[(3S)-3-phenylpyrrolidine-1-carbonyl]-3,4-dihydropyrimidin-4-one    (132),-   2-butyl-3-[1-(2-chlorophenyl)ethyl]-6-hydroxy-5-[(3S)-3-phenylpyrrolidine-1-carbonyl]-3,4-dihydropyrimidin-4-one    (133),-   2-butyl-3-[1-(2-chlorophenyl)ethyl]-6-hydroxy-5-[(3R)-3-phenylpyrrolidine-1-carbonyl]-3,4-dihydropyrimidin-4-one    (134),-   2-butyl-6-hydroxy-3-[(1R)-1-(2-methoxyphenyl)ethyl]-5-[(3S)-3-phenylpyrrolidine-1-carbonyl]-3,4-dihydropyrimidin-4-one    (135),-   2-butyl-6-hydroxy-3-(1-phenylethyl)-5-[(3S)-3-phenylpyrrolidine-1-carbonyl]-3,4-dihydropyrimidin-4-one    (136),-   2-butyl-6-hydroxy-3-[(1S)-1-phenylbutyl]-5-[(3R)-3-phenylpyrrolidine-1-carbonyl]-3,4-dihydropyrimidin-4-one    (137),-   3-[(1S)-1-{2-butyl-4-hydroxy-6-oxo-5-[(3R)-3-phenylpyrrolidine-1-carbonyl]-1,6-dihydropyrimidin-1-yl}ethyl]benzonitrile    (138),-   2-butyl-6-hydroxy-3-[(1S)-1-(3-methoxyphenyl)ethyl]-5-[(3R)-3-phenylpyrrolidine-1-carbonyl]-3,4-dihydropyrimidin-4-one    (139),-   2-butyl-6-hydroxy-5-[(3R)-3-phenylpyrrolidine-1-carbonyl]-3-[1-(pyridin-3-yl)ethyl]-3,4-dihydropyrimidin-4-one    (140),-   2-butyl-6-hydroxy-3-[(1S)-1-phenylethyl]-5-[(3R)-3-phenylpyrrolidine-1-carbonyl]-3,4-dihydropyrimidin-4-one    (141),-   2-butyl-3-[(1R)-1-cyclopropylethyl]-6-hydroxy-5-[(3R)-3-phenylpyrrolidine-1-carbonyl]-3,4-dihydropyrimidin-4-one    (142),-   2-butyl-3-[(1S)-1-(4-fluorophenyl)ethyl]-6-hydroxy-5-[(3S)-3-phenylpyrrolidine-1-carbonyl]-3,4-dihydropyrimidin-4-one    (143),-   2-butyl-6-hydroxy-5-[(3S)-3-phenylpyrrolidine-1-carbonyl]-3-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-3,4-dihydropyrimidin-4-one    (144),-   2-butyl-3-[(1R)-2,3-dihydro-1H-inden-1-yl]-6-hydroxy-5-[(3R)-3-phenylpyrrolidine-1-carbonyl]-3,4-dihydropyrimidin-4-one    (145),-   2-butyl-6-hydroxy-5-[(3S)-3-phenylpyrrolidine-1-carbonyl]-3-[1-(pyridin-3-yl)ethyl]-3,4-dihydropyrimidin-4-one    (146),-   2-butyl-6-hydroxy-5-[(3R)-3-phenylpyrrolidine-1-carbonyl]-3-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-3,4-dihydropyrimidin-4-one    (147),-   2-butyl-6-hydroxy-5-[(3R)-3-phenylpyrrolidine-1-carbonyl]-3-[1-(pyridin-4-yl)ethyl]-3,4-dihydropyrimidin-4-one    (148),-   3-[(1S)-1-{2-butyl-4-hydroxy-6-oxo-5-[(3S)-3-phenylpyrrolidine-1-carbonyl]-1,6-dihydropyrimidin-1-yl}ethyl]benzonitrile    (149),-   2-butyl-6-hydroxy-5-[(3R)-3-phenylpyrrolidine-1-carbonyl]-3-(propan-2-yl)-3,4-dihydropyrimidin-4-one    (150),-   2-butyl-6-hydroxy-3-[(1S)-1-(2-methoxyphenyl)ethyl]-5-[(3S)-3-phenylpyrrolidine-1-carbonyl]-3,4-dihydropyrimidin-4-one    (151),-   2-butyl-6-hydroxy-3-[(1S)-2-methoxy-1-phenylethyl]-5-[(3R)-3-phenylpyrrolidine-1-carbonyl]-3,4-dihydropyrimidin-4-one    (152),-   2-butyl-6-hydroxy-3-[(1S)-1-phenylbutyl]-5-[(3S)-3-phenylpyrrolidine-1-carbonyl]-3,4-dihydropyrimidin-4-one    (153),-   2-butyl-6-hydroxy-3-[(1S)-2-methoxy-1-phenylethyl]-5-[(3S)-3-phenylpyrrolidine-1-carbonyl]-3,4-dihydropyrimidin-4-one    (154),-   2-butyl-3-[(1R)-1-cyclopropylethyl]-6-hydroxy-5-[(3S)-3-phenylpyrrolidine-1-carbonyl]-3,4-dihydropyrimidin-4-one    (155),-   2-butyl-6-hydroxy-3-[(1S)-1-(2-methoxyphenyl)ethyl]-5-[(3R)-3-phenylpyrrolidine-1-carbonyl]-3,4-dihydropyrimidin-4-one    (156),-   2-butyl-3-[(1S)-1-(4-fluorophenyl)ethyl]-6-hydroxy-5-[(3R)-3-phenylpyrrolidine-1-carbonyl]-3,4-dihydropyrimidin-4-one    (157),-   2-butyl-3-[(1R)-2,3-dihydro-1H-inden-1-yl]-6-hydroxy-5-[(3S)-3-phenylpyrrolidine-1-carbonyl]-3,4-dihydropyrimidin-4-one    (158),-   2-butyl-6-hydroxy-5-[(3S)-3-phenylpyrrolidine-1-carbonyl]-3-(propan-2-yl)-3,4-dihydropyrimidin-4-one    (159),-   1-(2,6-dimethoxyphenyl)-6-hydroxy-5-[3-(2-methoxyphenyl)pyrrolidine-1-carbonyl]-2-[(propan-2-yloxy)methyl]-1,4-dihydropyrimidin-4-one    (160),-   1-(2,6-dimethoxyphenyl)-6-hydroxy-5-[3-(2-methoxyphenyl)pyrrolidine-1-carbonyl]-2-[(propan-2-yloxy)methyl]-1,4-dihydropyrimidin-4-one    (161),-   5-[3-(2,4-difluorophenyl)pyrrolidine-1-carbonyl]-1-(2,6-dimethoxyphenyl)-6-hydroxy-2-[(propan-2-yloxy)methyl]-1,4-dihydropyrimidin-4-one    (162),-   5-[3-(2,4-difluorophenyl)pyrrolidine-1-carbonyl]-1-(2,6-dimethoxyphenyl)-6-hydroxy-2-[(propan-2-yloxy)methyl]-1,4-dihydropyrimidin-4-one    (163),-   5-[3-(2,6-difluorophenyl)pyrrolidine-1-carbonyl]-1-(2,6-dimethoxyphenyl)-6-hydroxy-2-[(propan-2-yloxy)methyl]-1,4-dihydropyrimidin-4-one    (164),-   2-{1-[1-(2,6-dimethoxyphenyl)-6-hydroxy-4-oxo-2-[(propan-2-yloxy)methyl]-1,4-dihydropyrimidine-5-carbonyl]pyrrolidin-3-yl}benzonitrile    (165),-   5-[3-(2,6-difluorophenyl)pyrrolidine-1-carbonyl]-1-(2,6-dimethoxyphenyl)-6-hydroxy-2-[(propan-2-yloxy)methyl]-1,4-dihydropyrimidin-4-one    (166),-   2-{1-[1-(2,6-dimethoxyphenyl)-6-hydroxy-4-oxo-2-[(propan-2-yloxy)methyl]-1,4-dihydropyrimidine-5-carbonyl]pyrrolidin-3-yl}benzonitrile    (167),-   2-(2-cyclopropylethyl)-5-[3-(3,5-difluoropyridin-2-yl)pyrrolidine-1-carbonyl]-1-(2,6-dimethoxyphenyl)-6-hydroxy-1,4-dihydropyrimidin-4-one    (168),-   2-(2-cyclopropylethyl)-5-[3-(3,5-difluoropyridin-2-yl)pyrrolidine-1-carbonyl]-1-(2,6-dimethoxyphenyl)-6-hydroxy-1,4-dihydropyrimidin-4-one    (169),-   5-[3-(5-chloropyridin-2-yl)pyrrolidine-1-carbonyl]-2-(2-cyclopropylethyl)-1-(2,6-dimethoxyphenyl)-6-hydroxy-1,4-dihydropyrimidin-4-one    (170),-   5-[3-(5-chloropyridin-2-yl)pyrrolidine-1-carbonyl]-2-(2-cyclopropylethyl)-1-(2,6-dimethoxyphenyl)-6-hydroxy-1,4-dihydropyrimidin-4-one    (171),-   5-[3-(5-chloropyridin-2-yl)-2,5-dihydro-1H-pyrrole-1-carbonyl]-2-(2-cyclopropylethyl)-1-(2,6-dimethoxyphenyl)-6-hydroxy-1,4-dihydropyrimidin-4-one    (172),-   2-(2-cyclopropylethyl)-5-{4-[(2,3-difluorophenyl)methyl]piperazine-1-carbonyl}-1-(2,6-dimethoxyphenyl)-6-hydroxy-1,4-dihydropyrimidin-4-one    (173),-   5-[3-(5-chloro-3-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-1-(2,6-diethylphenyl)-6-hydroxy-2-(1-methyl-1H-pyrazol-3-yl)-1,4-dihydropyrimidin-4-one    (174),-   2-(2-cyclopropylethyl)-1-(2,6-dimethoxyphenyl)-5-[3-(5-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-6-hydroxy-1,4-dihydropyrimidin-4-one    (175),-   5-[3-(5-chloro-3-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-2-(2-cyclopropylethyl)-1-(2,6-dimethoxyphenyl)-6-hydroxy-1,4-dihydropyrimidin-4-one    (176),-   2-(2-cyclopropylethyl)-1-(2,6-dimethoxyphenyl)-5-[3-(5-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-6-hydroxy-1,4-dihydropyrimidin-4-one    (177),-   2-(2-cyclopropylethyl)-1-(2,6-dimethoxyphenyl)-5-[3-(3-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-6-hydroxy-1,4-dihydropyrimidin-4-one    (178),-   2-(2-cyclopropylethyl)-1-(2,6-dimethoxyphenyl)-5-[3-(3-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-6-hydroxy-1,4-dihydropyrimidin-4-one    (179),-   5-[3-(5-chloro-3-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-2-(2-cyclopropylethyl)-1-(2,6-dimethoxyphenyl)-6-hydroxy-1,4-dihydropyrimidin-4-one    (180),-   1-[(1S)-1-(3,5-difluorophenyl)propyl]-2-(1-ethyl-1H-pyrazol-3-yl)-5-[3-(3-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-6-hydroxy-1,4-dihydropyrimidin-4-one    (181),-   1-[(1S)-1-(3,5-difluorophenyl)propyl]-5-[3-(3,5-difluoropyridin-2-yl)pyrrolidine-1-carbonyl]-6-hydroxy-2-(1-methyl-1H-pyrazol-4-yl)-1,4-dihydropyrimidin-4-one    (182),-   5-[3-(5-chloropyridin-2-yl)pyrrolidine-1-carbonyl]-1-[(1S)-1-(3,5-difluorophenyl)propyl]-6-hydroxy-2-(1-methyl-1H-pyrazol-4-yl)-1,4-dihydropyrimidin-4-one    (183),-   1-[(1S)-1-(3,5-difluorophenyl)propyl]-5-[3-(3,5-difluoropyridin-2-yl)pyrrolidine-1-carbonyl]-6-hydroxy-2-(1-methyl-1H-pyrazol-3-yl)-1,4-dihydropyrimidin-4-one    (184),-   1-[(1S)-1-(3,5-difluorophenyl)propyl]-5-[3-(5-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-6-hydroxy-2-(1-methyl-1H-pyrazol-3-yl)-1,4-dihydropyrimidin-4-one    (185),-   1-[(1S)-1-(3,5-difluorophenyl)propyl]-2-(1-ethyl-1H-pyrazol-3-yl)-5-[3-(3-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-6-hydroxy-1,4-dihydropyrimidin-4-one    (186),-   5-[3-(5-chloropyridin-2-yl)pyrrolidine-1-carbonyl]-1-[(1S)-1-(3,5-difluorophenyl)propyl]-6-hydroxy-2-(1-methyl-1H-pyrazol-4-yl)-1,4-dihydropyrimidin-4-one    (187),-   1-[(1S)-1-(3,5-difluorophenyl)propyl]-5-[3-(3,5-difluoropyridin-2-yl)pyrrolidine-1-carbonyl]-6-hydroxy-2-(1-methyl-1H-pyrazol-4-yl)-1,4-dihydropyrimidin-4-one    (188),-   1-[(1S)-1-(3,5-difluorophenyl)propyl]-5-[3-(3-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-6-hydroxy-2-(1-methyl-1H-pyrazol-3-yl)-1,4-dihydropyrimidin-4-one    (189),-   5-[3-(5-chloropyridin-2-yl)pyrrolidine-1-carbonyl]-1-[(1S)-1-(3,5-difluorophenyl)propyl]-6-hydroxy-2-(1-methyl-1H-pyrazol-3-yl)-1,4-dihydropyrimidin-4-one    (190),-   1-[(1S)-1-(3,5-difluorophenyl)propyl]-5-[3-(5-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-6-hydroxy-2-(1-methyl-1H-pyrazol-4-yl)-1,4-dihydropyrimidin-4-one    (191),-   1-[(1S)-1-(3,5-difluorophenyl)propyl]-5-[3-(3,5-difluoropyridin-2-yl)pyrrolidine-1-carbonyl]-2-(1-ethyl-1H-pyrazol-3-yl)-6-hydroxy-1,4-dihydropyrimidin-4-one    (192),-   1-[(1S)-1-(3,5-difluorophenyl)propyl]-5-[3-(2-fluorophenyl)pyrrolidine-1-carbonyl]-6-hydroxy-2-(1-methyl-1H-pyrazol-3-yl)-1,4-dihydropyrimidin-4-one    (193),-   1-[(1S)-1-(3,5-difluorophenyl)propyl]-5-[3-(4-fluorophenyl)pyrrolidine-1-carbonyl]-6-hydroxy-2-(1-methyl-1H-pyrazol-3-yl)-1,4-dihydropyrimidin-4-one    (194),-   1-[(1S)-1-(3,5-difluorophenyl)propyl]-6-hydroxy-5-[3-(2-methoxyphenyl)pyrrolidine-1-carbonyl]-2-(1-methyl-1H-pyrazol-3-yl)-1,4-dihydropyrimidin-4-one    (195),-   1-[(1S)-1-(3,5-difluorophenyl)propyl]-5-[3-(2-fluorophenyl)pyrrolidine-1-carbonyl]-6-hydroxy-2-(1-methyl-1H-pyrazol-4-yl)-1,4-dihydropyrimidin-4-one    (196),-   1-[(1S)-1-(3,5-difluorophenyl)propyl]-5-[3-(4-fluorophenyl)pyrrolidine-1-carbonyl]-6-hydroxy-2-(1-methyl-1H-pyrazol-4-yl)-1,4-dihydropyrimidin-4-one    (197),-   1-[(1S)-1-(3,5-difluorophenyl)propyl]-6-hydroxy-5-[3-(2-methoxyphenyl)pyrrolidine-1-carbonyl]-2-(1-methyl-1H-pyrazol-4-yl)-1,4-dihydropyrimidin-4-one    (198),-   1-[(1S)-1-(3,5-difluorophenyl)propyl]-5-[3-(5-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-6-hydroxy-2-(1-methyl-1H-pyrazol-3-yl)-1,4-dihydropyrimidin-4-one    (199),-   1-[(1S)-1-(3,5-difluorophenyl)propyl]-5-[3-(4-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-6-hydroxy-2-(1-methyl-1H-pyrazol-3-yl)-1,4-dihydropyrimidin-4-one    (200),-   1-[(1S)-1-(3,5-difluorophenyl)propyl]-5-[3-(3-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-6-hydroxy-2-(1-methyl-1H-pyrazol-3-yl)-1,4-dihydropyrimidin-4-one    (201),-   1-[(1S)-1-(3,5-difluorophenyl)propyl]-2-(1-ethyl-1H-pyrazol-3-yl)-5-[3-(4-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-6-hydroxy-1,4-dihydropyrimidin-4-one    (202),-   1-[(1S)-1-(3,5-difluorophenyl)propyl]-5-[3-(4-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-6-hydroxy-2-(1-methyl-1H-pyrazol-4-yl)-1,4-dihydropyrimidin-4-one    (203),-   1-[(1S)-1-(3,5-difluorophenyl)propyl]-5-[3-(3-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-6-hydroxy-2-(4-methyl-1,3-thiazol-2-yl)-1,4-dihydropyrimidin-4-one    (204),-   1-((S)-1-(3,5-difluorophenyl)propyl)-5-(3-(4-fluoropyridin-2-yl)pyrrolidine-1-carbonyl)-6-hydroxy-2-(4-methylthiazol-2-yl)pyrimidin-4(1H)-one    (205),-   1-[(1S)-1-(3,5-difluorophenyl)propyl]-5-[3-(5-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-6-hydroxy-2-(4-methyl-1,3-thiazol-2-yl)-1,4-dihydropyrimidin-4-one    (206),-   1-[(1S)-1-(3,5-difluorophenyl)propyl]-6-hydroxy-5-[3-(2-methoxyphenyl)pyrrolidine-1-carbonyl]-2-(4-methyl-1,3-thiazol-2-yl)-1,4-dihydropyrimidin-4-one    (207),-   1-[(1S)-1-(3,5-difluorophenyl)propyl]-5-[3-(2-fluorophenyl)pyrrolidine-1-carbonyl]-6-hydroxy-2-(4-methyl-1,3-thiazol-2-yl)-1,4-dihydropyrimidin-4-one    (208),-   5-[3-(5-chloropyridin-2-yl)pyrrolidine-1-carbonyl]-1-[(1S)-1-(3,5-difluorophenyl)propyl]-6-hydroxy-2-(4-methyl-1,3-thiazol-2-yl)-1,4-dihydropyrimidin-4-one    (209),-   1-[(1S)-1-(3,5-difluorophenyl)propyl]-5-[3-(3,5-difluoropyridin-2-yl)pyrrolidine-1-carbonyl]-6-hydroxy-2-(4-methyl-1,3-thiazol-2-yl)-1,4-dihydropyrimidin-4-one    (210),-   1-[(1S)-1-(3,5-difluorophenyl)propyl]-5-[3-(4-fluorophenyl)pyrrolidine-1-carbonyl]-6-hydroxy-2-(4-methyl-1,3-thiazol-2-yl)-1,4-dihydropyrimidin-4-one    (211),-   1-[(1S)-1-(3,5-difluorophenyl)propyl]-2-(1-ethyl-1H-pyrazol-3-yl)-5-[3-(3-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-6-hydroxy-1,4-dihydropyrimidin-4-one    (212),-   5-[3-(5-chloropyridin-2-yl)pyrrolidine-1-carbonyl]-1-[(1S)-1-(3,5-difluorophenyl)propyl]-2-(1-ethyl-1H-pyrazol-3-yl)-6-hydroxy-1,4-dihydropyrimidin-4-one    (213),-   5-[3-(5-chloro-3-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-1-[(1S)-1-(3,5-difluorophenyl)propyl]-2-(1-ethyl-1H-pyrazol-3-yl)-6-hydroxy-1,4-dihydropyrimidin-4-one    (214),-   1-[(1S)-1-(3,5-difluorophenyl)propyl]-5-[3-(3,5-difluoropyridin-2-yl)pyrrolidine-1-carbonyl]-2-(1-ethyl-1H-pyrazol-3-yl)-6-hydroxy-1,4-dihydropyrimidin-4-one    (215),-   1-[(1S)-1-(3,5-difluorophenyl)propyl]-2-(1-ethyl-1H-pyrazol-3-yl)-5-[3-(5-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-6-hydroxy-1,4-dihydropyrimidin-4-one    (216),-   1-[(1S)-1-(3,5-difluorophenyl)propyl]-5-[3-(3,5-difluoropyridin-2-yl)pyrrolidine-1-carbonyl]-6-hydroxy-2-(1-methyl-1H-pyrazol-4-yl)-1,4-dihydropyrimidin-4-one    (217),-   5-[3-(5-chloropyridin-2-yl)pyrrolidine-1-carbonyl]-1-[(1S)-1-(3,5-difluorophenyl)propyl]-6-hydroxy-2-(1-methyl-1H-pyrazol-4-yl)-1,4-dihydropyrimidin-4-one    (218),-   1-[(1S)-1-(3,5-difluorophenyl)propyl]-5-[3-(3-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-6-hydroxy-2-(1-methyl-1H-pyrazol-4-yl)-1,4-dihydropyrimidin-4-one    (219),-   1-[(1S)-1-(3,5-difluorophenyl)propyl]-5-[3-(5-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-6-hydroxy-2-(1-methyl-1H-pyrazol-4-yl)-1,4-dihydropyrimidin-4-one    (220),-   1-(2,6-diethylphenyl)-6-hydroxy-2-[(propan-2-yloxy)methyl]-5-[3-(pyridin-4-yl)pyrrolidine-1-carbonyl]-1,4-dihydropyrimidin-4-one    (221),-   5-[4-(6-chloropyridin-3-yl)piperidine-1-carbonyl]-3-(2,6-diethylphenyl)-6-hydroxy-2-[(propan-2-yloxy)methyl]-3,4-dihydropyrimidin-4-one    (222),-   5-[3-(4-chlorophenyl)pyrrolidine-1-carbonyl]-1-(2,6-dimethoxyphenyl)-2-(4-fluorophenyl)-6-hydroxy-1,4-dihydropyrimidin-4-one    (223),-   1-(2,6-dimethoxyphenyl)-2-(4-fluorophenyl)-6-hydroxy-5-[3-(pyridin-4-yl)pyrrolidine-1-carbonyl]-1,4-dihydropyrimidin-4-one    (224),-   1-(2,6-dimethoxyphenyl)-2-(4-fluorophenyl)-5-[3-(2-fluorophenyl)pyrrolidine-1-carbonyl]-6-hydroxy-1,4-dihydropyrimidin-4-one    (225),-   2-(cyclopropylmethyl)-1-(2,6-dimethoxyphenyl)-5-[3-(2-fluorophenyl)pyrrolidine-1-carbonyl]-6-hydroxy-1,4-dihydropyrimidin-4-one    (226),-   5-[4-(6-chloropyridin-3-yl)piperidine-1-carbonyl]-2-(cyclopropylmethyl)-1-(2,6-dimethoxyphenyl)-6-hydroxy-1,4-dihydropyrimidin-4-one    (227),-   5-[3-(4-chlorophenyl)pyrrolidine-1-carbonyl]-2-(cyclopropylmethyl)-1-(2,6-dimethoxyphenyl)-6-hydroxy-1,4-dihydropyrimidin-4-one    (228),-   5-[3-(2-chlorophenyl)pyrrolidine-1-carbonyl]-1-(2,6-dimethoxyphenyl)-2-(4-fluorophenyl)-6-hydroxy-1,4-dihydropyrimidin-4-one    (229),-   2-(cyclopropylmethyl)-1-(2,6-dimethoxyphenyl)-6-hydroxy-5-[3-(pyridin-4-yl)pyrrolidine-1-carbonyl]-1,4-dihydropyrimidin-4-one    (230),-   1-(2,6-dimethoxyphenyl)-2-[(4-fluorophenyl)methyl]-5-[3-(2-fluorophenyl)pyrrolidine-1-carbonyl]-6-hydroxy-1,4-dihydropyrimidin-4-one    (231),-   1-(2,6-dimethoxyphenyl)-5-[3-(4-fluorophenyl)pyrrolidine-1-carbonyl]-6-hydroxy-2-(5-methylpyridin-3-yl)-1,4-dihydropyrimidin-4-one    (232),-   1-(2,6-dimethoxyphenyl)-5-[3-(2-fluorophenyl)pyrrolidine-1-carbonyl]-6-hydroxy-2-(5-methylpyridin-3-yl)-1,4-dihydropyrimidin-4-one    (233),-   1-(2,6-dimethoxyphenyl)-6-hydroxy-5-[3-(2-methoxyphenyl)pyrrolidine-1-carbonyl]-2-(5-methylpyridin-3-yl)-1,4-dihydropyrimidin-4-one    (234),-   5-[3-(3,5-difluoropyridin-2-yl)pyrrolidine-1-carbonyl]-1-(2,6-dimethoxyphenyl)-6-hydroxy-2-(6-methylpyridin-2-yl)-1,4-dihydropyrimidin-4-one    (235),-   1-(2,6-dimethoxyphenyl)-5-[3-(2-fluorophenyl)pyrrolidine-1-carbonyl]-6-hydroxy-2-(6-methylpyridin-2-yl)-1,4-dihydropyrimidin-4-one    (236),-   2-{1-[2-(3-chlorophenyl)-1-(2,6-dimethoxyphenyl)-6-hydroxy-4-oxo-1,4-dihydropyrimidine-5-carbonyl]pyrrolidin-3-yl}benzonitrile    (237),-   2-(3-chlorophenyl)-5-[3-(3,5-difluoropyridin-2-yl)pyrrolidine-1-carbonyl]-1-(2,6-dimethoxyphenyl)-6-hydroxy-1,4-dihydropyrimidin-4-one    (238),-   1-(2,6-dimethoxyphenyl)-5-[3-(2-fluorophenyl)pyrrolidine-1-carbonyl]-6-hydroxy-2-(4-methylpyridin-2-yl)-1,4-dihydropyrimidin-4-one    (239),-   2-{1-[1-(2,6-dimethoxyphenyl)-6-hydroxy-2-(4-methylpyridin-2-yl)-4-oxo-1,4-dihydropyrimidine-5-carbonyl]pyrrolidin-3-yl}benzonitrile    (240),-   5-[3-(2,6-difluorophenyl)pyrrolidine-1-carbonyl]-1-(2,6-dimethoxyphenyl)-6-hydroxy-2-(3-methylphenyl)-1,4-dihydropyrimidin-4-one    (241),-   2-{1-[1-(2,6-dimethoxyphenyl)-6-hydroxy-2-(3-methylphenyl)-4-oxo-1,4-dihydropyrimidine-5-carbonyl]pyrrolidin-3-yl}benzonitrile    (242),-   2-{1-[2-(5-chloropyridin-3-yl)-1-(2,6-dimethoxyphenyl)-6-hydroxy-4-oxo-1,4-dihydropyrimidine-5-carbonyl]pyrrolidin-3-yl}benzonitrile    (243),-   5-[3-(3,5-difluoropyridin-2-yl)pyrrolidine-1-carbonyl]-1-(2,6-dimethoxyphenyl)-6-hydroxy-2-(3-methylphenyl)-1,4-dihydropyrimidin-4-one    (244),-   1-(2,6-dimethoxyphenyl)-5-[3-(3-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-6-hydroxy-2-(3-methoxyphenyl)-1,4-dihydropyrimidin-4-one    (245),-   5-[3-(3,5-difluoropyridin-2-yl)pyrrolidine-1-carbonyl]-1-(2,6-dimethoxyphenyl)-6-hydroxy-2-(3-methoxyphenyl)-1,4-dihydropyrimidin-4-one    (246),-   2-(5-chloropyridin-3-yl)-5-[3-(2,6-difluorophenyl)pyrrolidine-1-carbonyl]-1-(2,6-dimethoxyphenyl)-6-hydroxy-1,4-dihydropyrimidin-4-one    (247),-   5-[3-(2,4-difluorophenyl)pyrrolidine-1-carbonyl]-1-(2,6-dimethoxyphenyl)-6-hydroxy-2-(1-methyl-1H-pyrazol-4-yl)-1,4-dihydropyrimidin-4-one    (248),-   5-[3-(2,6-difluorophenyl)pyrrolidine-1-carbonyl]-1-(2,6-dimethoxyphenyl)-6-hydroxy-2-(1-methyl-1H-pyrazol-4-yl)-1,4-dihydropyrimidin-4-one    (249),-   5-[3-(2,4-difluorophenyl)pyrrolidine-1-carbonyl]-1-(2,6-dimethoxyphenyl)-6-hydroxy-2-(1-methyl-1H-pyrazol-3-yl)-1,4-dihydropyrimidin-4-one    (25),-   5-[3-(2,6-difluorophenyl)pyrrolidine-1-carbonyl]-1-(2,6-dimethoxyphenyl)-6-hydroxy-2-(1-methyl-1H-pyrazol-3-yl)-1,4-dihydropyrimidin-4-one    (251),-   5-[3-(2,6-difluorophenyl)pyrrolidine-1-carbonyl]-1-(2,6-dimethoxyphenyl)-6-hydroxy-2-(6-methylpyridin-3-yl)-1,4-dihydropyrimidin-4-one    (252),-   5-[3-(2,4-difluorophenyl)pyrrolidine-1-carbonyl]-1-(2,6-dimethoxyphenyl)-6-hydroxy-2-(6-methylpyridin-3-yl)-1,4-dihydropyrimidin-4-one    (253),-   5-[3-(2,4-difluorophenyl)pyrrolidine-1-carbonyl]-1-(2,6-dimethoxyphenyl)-6-hydroxy-2-(2-methylpyridin-4-yl)-1,4-dihydropyrimidin-4-one    (254),-   1-(2,6-dimethoxyphenyl)-2-(4-fluoro-3-methylphenyl)-5-[3-(3-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-6-hydroxy-1,4-dihydropyrimidin-4-one    (255),-   5-[3-(3,5-difluoropyridin-2-yl)pyrrolidine-1-carbonyl]-1-(2,6-dimethoxyphenyl)-2-(4-fluoro-3-methylphenyl)-6-hydroxy-1,4-dihydropyrimidin-4-one    (256),-   5-[3-(2,6-difluorophenyl)pyrrolidine-1-carbonyl]-1-(2,6-dimethoxyphenyl)-6-hydroxy-2-(2-methylpyridin-4-yl)-1,4-dihydropyrimidin-4-one    (257),-   1-(2,6-diethylphenyl)-5-[3-(3,5-difluoropyridin-2-yl)pyrrolidine-1-carbonyl]-6-hydroxy-2-(1-methyl-1H-pyrazol-3-yl)-1,4-dihydropyrimidin-4-one    (258),-   5-[3-(5-chloro-3-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-1-(2,6-dimethoxyphenyl)-6-hydroxy-2-(1-methyl-1H-pyrazol-3-yl)-1,4-dihydropyrimidin-4-one    (259),-   2-(5-chloropyridin-3-yl)-5-[3-(2,4-difluorophenyl)pyrrolidine-1-carbonyl]-1-(2,6-dimethoxyphenyl)-6-hydroxy-1,4-dihydropyrimidin-4-one    (260),-   5-[3-(5-chloro-3-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-1-(2,6-dimethoxyphenyl)-6-hydroxy-2-(3-methoxyphenyl)-1,4-dihydropyrimidin-4-one    (261),-   5-[3-(2,4-difluorophenyl)pyrrolidine-1-carbonyl]-1-(2,6-dimethoxyphenyl)-6-hydroxy-2-(4-methylpyridin-2-yl)-1,4-dihydropyrimidin-4-one    (262),-   5-[3-(5-chloro-3-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-1-(2,6-dimethoxyphenyl)-6-hydroxy-2-(3-methylphenyl)-1,4-dihydropyrimidin-4-one    (263),-   5-[3-(5-chloro-3-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-2-(3-chlorophenyl)-1-(2,6-dimethoxyphenyl)-6-hydroxy-1,4-dihydropyrimidin-4-one    (264),-   5-[3-(5-chloro-3-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-1-(2,6-dimethoxyphenyl)-2-(4-fluorophenyl)-6-hydroxy-1,4-dihydropyrimidin-4-one    (265),-   5-[3-(2,4-difluorophenyl)pyrrolidine-1-carbonyl]-1-(2,6-dimethoxyphenyl)-6-hydroxy-2-(2-methyl-1,3-thiazol-4-yl)-1,4-dihydropyrimidin-4-one    (266),-   1-(2,6-diethylphenyl)-5-[3-(2,6-difluorophenyl)pyrrolidine-1-carbonyl]-6-hydroxy-2-(1-methyl-1H-pyrazol-3-yl)-1,4-dihydropyrimidin-4-one    (267),-   1-(2,6-diethylphenyl)-5-[3-(2-fluorophenyl)pyrrolidine-1-carbonyl]-6-hydroxy-2-(1-methyl-1H-pyrazol-3-yl)-1,4-dihydropyrimidin-4-one    (268),-   5-[3-(2,4-difluorophenyl)pyrrolidine-1-carbonyl]-1-(2,6-dimethoxyphenyl)-2-(1-ethyl-1H-pyrazol-3-yl)-6-hydroxy-1,4-dihydropyrimidin-4-one    (269),-   5-[3-(2,6-difluorophenyl)pyrrolidine-1-carbonyl]-1-(2,6-dimethoxyphenyl)-6-hydroxy-2-(2-methyl-1,3-thiazol-4-yl)-1,4-dihydropyrimidin-4-one    (270),-   5-[3-(2,6-difluorophenyl)pyrrolidine-1-carbonyl]-1-(2,6-dimethoxyphenyl)-6-hydroxy-2-(4-methyl-1,3-thiazol-2-yl)-1,4-dihydropyrimidin-4-one    (271),-   1-(2,6-diethylphenyl)-5-[3-(4-fluorophenyl)pyrrolidine-1-carbonyl]-6-hydroxy-2-(1-methyl-1H-pyrazol-3-yl)-1,4-dihydropyrimidin-4-one    (272),-   5-[3-(2,6-difluorophenyl)pyrrolidine-1-carbonyl]-1-(2,6-dimethoxyphenyl)-6-hydroxy-2-(4-methoxypyridin-2-yl)-1,4-dihydropyrimidin-4-one    (273),-   5-[3-(2,6-difluorophenyl)pyrrolidine-1-carbonyl]-1-(2,6-dimethoxyphenyl)-6-hydroxy-2-(5-methylpyridin-2-yl)-1,4-dihydropyrimidin-4-one    (274),-   1-(2,6-diethylphenyl)-5-[3-(3-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-6-hydroxy-2-(1-methyl-1H-pyrazol-3-yl)-1,4-dihydropyrimidin-4-one    (275),-   5-[3-(2,6-difluorophenyl)pyrrolidine-1-carbonyl]-1-(2,6-dimethoxyphenyl)-2-(1-ethyl-1H-pyrazol-3-yl)-6-hydroxy-1,4-dihydropyrimidin-4-one    (276),-   5-[4-(2,3-difluorophenoxy)piperidine-1-carbonyl]-1-(2,6-dimethoxyphenyl)-6-hydroxy-2-(2-methyl-1,3-thiazol-4-yl)-1,4-dihydropyrimidin-4-one    (277),-   5-[3-(2,4-difluorophenyl)pyrrolidine-1-carbonyl]-1-(2,6-dimethoxyphenyl)-6-hydroxy-2-(4-methoxypyridin-2-yl)-1,4-dihydropyrimidin-4-one    (278),-   2-(6-chloropyridin-3-yl)-5-[3-(2,4-difluorophenyl)pyrrolidine-1-carbonyl]-1-(2,6-dimethoxyphenyl)-6-hydroxy-1,4-dihydropyrimidin-4-one    (279),-   2-(5-chloropyridin-2-yl)-5-[3-(2,6-difluorophenyl)pyrrolidine-1-carbonyl]-1-(2,6-dimethoxyphenyl)-6-hydroxy-1,4-dihydropyrimidin-4-one    (280),-   2-(6-chloropyridin-3-yl)-5-[3-(2,6-difluorophenyl)pyrrolidine-1-carbonyl]-1-(2,6-dimethoxyphenyl)-6-hydroxy-1,4-dihydropyrimidin-4-one    (281),-   5-[3-(2,4-difluorophenyl)pyrrolidine-1-carbonyl]-1-(2,6-dimethoxyphenyl)-6-hydroxy-2-(5-methylpyridin-2-yl)-1,4-dihydropyrimidin-4-one    (282),-   1-(2,6-diethylphenyl)-6-hydroxy-2-(1-methyl-1H-pyrazol-3-yl)-5-[(3R)-3-phenylpyrrolidine-1-carbonyl]-1,4-dihydropyrimidin-4-one    (283),-   1-(2,6-dimethoxyphenyl)-2-(1-ethyl-1H-pyrazol-3-yl)-6-hydroxy-5-[(3R)-3-phenylpyrrolidine-1-carbonyl]-1,4-dihydropyrimidin-4-one    (284),-   1-(2,6-diethylphenyl)-6-hydroxy-2-(1-methyl-1H-pyrazol-3-yl)-5-[(3S)-3-phenylpyrrolidine-1-carbonyl]-1,4-dihydropyrimidin-4-one    (285),-   1-(2,6-dimethoxyphenyl)-2-(1-ethyl-1H-pyrazol-3-yl)-6-hydroxy-5-[(3S)-3-phenylpyrrolidine-1-carbonyl]-1,4-dihydropyrimidin-4-one    (286),-   2-(5-chloropyridin-2-yl)-5-[3-(2,4-difluorophenyl)pyrrolidine-1-carbonyl]-1-(2,6-dimethoxyphenyl)-6-hydroxy-1,4-dihydropyrimidin-4-one    (287),-   2-(1-ethyl-1H-pyrazol-3-yl)-6-hydroxy-5-[(3S)-3-phenylpyrrolidine-1-carbonyl]-1-[3-(propan-2-yl)phenyl]-1,4-dihydropyrimidin-4-one    (288),-   1-(2,6-diethylphenyl)-6-hydroxy-5-[(3S)-3-phenylpyrrolidine-1-carbonyl]-2-[1-(propan-2-yl)-1H-pyrazol-3-yl]-1,4-dihydropyrimidin-4-one    (289),-   5-[3-(5-chloro-3-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-1-(2,6-diethylphenyl)-6-hydroxy-2-[1-(propan-2-yl)-1H-pyrazol-3-yl]-1,4-dihydropyrimidin-4-one    (290),-   2-(1-ethyl-1H-pyrazol-3-yl)-6-hydroxy-5-[(3R)-3-phenylpyrrolidine-1-carbonyl]-1-[3-(propan-2-yl)phenyl]-1,4-dihydropyrimidin-4-one    (291),-   1-(2,6-diethylphenyl)-5-[3-(3-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-6-hydroxy-2-[1-(propan-2-yl)-1H-pyrazol-3-yl]-1,4-dihydropyrimidin-4-one    (292),-   5-[3-(3,5-difluoropyridin-2-yl)pyrrolidine-1-carbonyl]-2-(1-ethyl-1H-pyrazol-3-yl)-6-hydroxy-1-[3-(propan-2-yl)phenyl]-1,4-dihydropyrimidin-4-one    (293),-   2-(1-ethyl-1H-pyrazol-3-yl)-5-[3-(2-fluorophenyl)pyrrolidine-1-carbonyl]-6-hydroxy-1-[3-(propan-2-yl)phenyl]-1,4-dihydropyrimidin-4-one    (294),-   1-(2,6-diethylphenyl)-5-[3-(2-fluorophenyl)pyrrolidine-1-carbonyl]-6-hydroxy-2-[1-(propan-2-yl)-1H-pyrazol-3-yl]-1,4-dihydropyrimidin-4-one    (295),-   5-[3-(5-chloro-3-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-1-(2,6-diethylphenyl)-6-hydroxy-2-(2-methyl-1,3-thiazol-4-yl)-1,4-dihydropyrimidin-4-one    (296),-   1-(2,6-diethylphenyl)-5-[3-(3,5-difluoropyridin-2-yl)pyrrolidine-1-carbonyl]-6-hydroxy-2-[2-(propan-2-yl)-1,3-thiazol-4-yl]-1,4-dihydropyrimidin-4-one    (297),-   1-(2,6-diethylphenyl)-5-[3-(3,5-difluoropyridin-2-yl)pyrrolidine-1-carbonyl]-6-hydroxy-2-(2-methyl-1,3-thiazol-4-yl)-1,4-dihydropyrimidin-4-one    (298),-   1-(2,6-diethylphenyl)-6-hydroxy-5-[(3S)-3-phenylpyrrolidine-1-carbonyl]-2-[2-(propan-2-yl)-1,3-thiazol-4-yl]-1,4-dihydropyrimidin-4-one    (299),-   1-(2,6-diethylphenyl)-5-[3-(5-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-6-hydroxy-2-[2-(propan-2-yl)-1,3-thiazol-4-yl]-1,4-dihydropyrimidin-4-one    (300),-   1-(2,6-diethylphenyl)-6-hydroxy-2-(2-methyl-1,3-thiazol-4-yl)-5-[(3R)-3-phenylpyrrolidine-1-carbonyl]-1,4-dihydropyrimidin-4-one    (301),-   1-(2,6-diethylphenyl)-5-[3-(3-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-6-hydroxy-2-(2-methyl-1,3-thiazol-4-yl)-1,4-dihydropyrimidin-4-one    (302),-   1-(2,6-diethylphenyl)-6-hydroxy-2-(2-methyl-1,3-thiazol-4-yl)-5-[(3S)-3-phenylpyrrolidine-1-carbonyl]-1,4-dihydropyrimidin-4-one    (303),-   5-[3-(5-chloro-3-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-1-(2,6-diethylphenyl)-6-hydroxy-2-(1-methyl-1H-pyrazol-3-yl)-1,4-dihydropyrimidin-4-one    (304),-   1-(2,6-diethylphenyl)-5-[3-(2-fluorophenyl)pyrrolidine-1-carbonyl]-6-hydroxy-2-(1-methyl-1H-pyrazol-3-yl)-1,4-dihydropyrimidin-4-one    (305),-   5-[3-(5-chloro-3-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-1-(2,6-diethylphenyl)-6-hydroxy-2-(4-methyl-1,3-thiazol-2-yl)-1,4-dihydropyrimidin-4-one    (306),-   1-(2,6-diethylphenyl)-5-[3-(3-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-6-hydroxy-2-(4-methyl-1,3-thiazol-2-yl)-1,4-dihydropyrimidin-4-one    (307),-   1-(2,6-diethylphenyl)-2-(1-ethyl-1H-pyrazol-3-yl)-5-[3-(3-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-6-hydroxy-1,4-dihydropyrimidin-4-one    (308),-   1-(2,6-diethylphenyl)-5-[3-(3,5-difluoropyridin-2-yl)pyrrolidine-1-carbonyl]-2-(1-ethyl-1H-pyrazol-3-yl)-6-hydroxy-1,4-dihydropyrimidin-4-one    (309),-   1-(2,6-diethylphenyl)-2-(1-ethyl-1H-pyrazol-4-yl)-5-[3-(2-fluorophenyl)pyrrolidine-1-carbonyl]-6-hydroxy-1,4-dihydropyrimidin-4-one    (310),-   5-[3-(5-chloro-3-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-1-(2,6-diethylphenyl)-2-(1-ethyl-1H-pyrazol-3-yl)-6-hydroxy-1,4-dihydropyrimidin-4-one    (311),-   5-[3-(5-chloro-3-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-1-(2,6-diethylphenyl)-6-hydroxy-2-(4-methyl-1,3-thiazol-2-yl)-1,4-dihydropyrimidin-4-one    (312),-   5-[3-(5-chloro-3-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-1-(2,6-diethylphenyl)-2-(1-ethyl-1H-pyrazol-4-yl)-6-hydroxy-1,4-dihydropyrimidin-4-one    (313),-   2-(4-fluoro-3-methylphenyl)-6-hydroxy-1-[(1S)-1-phenylpropyl]-5-[(3R)-3-phenylpyrrolidine-1-carbonyl]-1,4-dihydropyrimidin-4-one    (314),-   1-(2,6-diethylphenyl)-5-[3-(3,5-difluoropyridin-2-yl)pyrrolidine-1-carbonyl]-2-(1-ethyl-1H-pyrazol-4-yl)-6-hydroxy-1,4-dihydropyrimidin-4-one    (315),-   2-(1-cyclopropyl-1H-pyrazol-3-yl)-1-(2,6-diethylphenyl)-6-hydroxy-5-[(3S)-3-phenylpyrrolidine-1-carbonyl]-1,4-dihydropyrimidin-4-one    (316),-   1-(2,6-diethylphenyl)-6-hydroxy-2-[1-(2-methylpropyl)-1H-pyrazol-3-yl]-5-[(3S)-3-phenylpyrrolidine-1-carbonyl]-1,4-dihydropyrimidin-4-one    (317),-   1-(2,6-diethylphenyl)-5-[3-(5-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-6-hydroxy-2-[1-(2-methylpropyl)-1H-pyrazol-3-yl]-1,4-dihydropyrimidin-4-one    (318),-   2-(1-cyclopropyl-1H-pyrazol-3-yl)-1-(2,6-diethylphenyl)-5-[3-(3-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-6-hydroxy-1,4-dihydropyrimidin-4-one    (319),-   1-(2,6-diethylphenyl)-5-[3-(3,5-difluoropyridin-2-yl)pyrrolidine-1-carbonyl]-6-hydroxy-2-[1-(2-methylpropyl)-1H-pyrazol-3-yl]-1,4-dihydropyrimidin-4-one    (320),-   5-[3-(3,5-difluoropyridin-2-yl)pyrrolidine-1-carbonyl]-6-hydroxy-2-(4-methyl-1,3-thiazol-2-yl)-1-[(1S)-1-phenylpropyl]-1,4-dihydropyrimidin-4-one    (321),-   5-[3-(5-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-6-hydroxy-2-(4-methyl-1,3-thiazol-2-yl)-1-[(1S)-1-phenylpropyl]-1,4-dihydropyrimidin-4-one    (322),-   5-[3-(5-chloro-3-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-6-hydroxy-2-(4-methyl-1,3-thiazol-2-yl)-1-[(1S)-1-phenylpropyl]-1,4-dihydropyrimidin-4-one    (323),-   5-[3-(2-fluorophenyl)pyrrolidine-1-carbonyl]-6-hydroxy-2-(4-methyl-1,3-thiazol-2-yl)-1-[(1S)-1-phenylpropyl]-1,4-dihydropyrimidin-4-one    (324),-   2-(1-cyclopropyl-1H-pyrazol-3-yl)-1-(2,6-diethylphenyl)-5-[3-(3,5-difluoropyridin-2-yl)pyrrolidine-1-carbonyl]-6-hydroxy-1,4-dihydropyrimidin-4-one    (325),-   5-[3-(5-chloro-3-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-1-[(1S)-1-(3,5-difluorophenyl)-2-methylpropyl]-2-(1-ethyl-1H-pyrazol-3-yl)-6-hydroxy-1,4-dihydropyrimidin-4-one    (326),-   1-[(1S)-1-(3,5-difluorophenyl)-2-methylpropyl]-5-[3-(3,5-difluoropyridin-2-yl)pyrrolidine-1-carbonyl]-2-(1-ethyl-1H-pyrazol-3-yl)-6-hydroxy-1,4-dihydropyrimidin-4-one    (327),-   2-(1-cyclopropyl-1H-pyrazol-3-yl)-1-(2,6-diethylphenyl)-5-[3-(5-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-6-hydroxy-1,4-dihydropyrimidin-4-one    (328),-   6-hydroxy-3-[(1R)-2-methoxy-1-phenylethyl]-5-[(3R)-3-phenylpyrrolidine-1-carbonyl]-2-propyl-3,4-dihydropyrimidin-4-one    (329),-   6-hydroxy-3-[(1R)-2-methoxy-1-phenylethyl]-5-[(3S)-3-phenylpyrrolidine-1-carbonyl]-2-propyl-3,4-dihydropyrimidin-4-one    (330),-   3-[(1S)-1-{2-butyl-4-hydroxy-6-oxo-5-[(3R)-3-phenylpyrrolidine-1-carbonyl]-1,6-dihydropyrimidin-1-yl}propyl]benzonitrile    (331),-   3-[(1S)-1-{2-butyl-5-[3-(3,5-difluoropyridin-2-yl)pyrrolidine-1-carbonyl]-4-hydroxy-6-oxo-1,6-dihydropyrimidin-1-yl}propyl]benzonitrile    (332),-   3-[(1S)-1-{2-butyl-5-[3-(3,5-difluoropyridin-2-yl)pyrrolidine-1-carbonyl]-4-hydroxy-6-oxo-1,6-dihydropyrimidin-1-yl}propyl]benzonitrile    (333),-   3-[(1S)-1-{4-hydroxy-6-oxo-5-[(3R)-3-phenylpyrrolidine-1-carbonyl]-2-[(propan-2-yloxy)methyl]-1,6-dihydropyrimidin-1-yl}propyl]benzonitrile    (334),-   3-[(1S)-1-{2-butyl-5-[3-(5-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-4-hydroxy-6-oxo-1,6-dihydropyrimidin-1-yl}propyl]benzonitrile    (335),-   3-[(1S)-1-{2-butyl-5-[3-(5-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-4-hydroxy-6-oxo-1,6-dihydropyrimidin-1-yl}propyl]benzonitrile    (336),-   3-[(S)-{2-butyl-5-[3-(5-chloropyridin-2-yl)pyrrolidine-1-carbonyl]-4-hydroxy-6-oxo-1,6-dihydropyrimidin-1-yl}(cyclopropyl)methyl]benzonitrile    (337),-   3-[(S)-{2-butyl-5-[3-(5-chloropyridin-2-yl)pyrrolidine-1-carbonyl]-4-hydroxy-6-oxo-1,6-dihydropyrimidin-1-yl}(cyclopropyl)methyl]benzonitrile    (338),-   3-[(1S)-1-{2-butyl-5-[3-(5-chloro-3-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-4-hydroxy-6-oxo-1,6-dihydropyrimidin-1-yl}propyl]benzonitrile    (339),-   2-butyl-5-[3-(3,5-difluoropyridin-2-yl)pyrrolidine-1-carbonyl]-6-hydroxy-3-[(1S)-1-(3-methoxyphenyl)propyl]-3,4-dihydropyrimidin-4-one    (340),-   2-butyl-5-[3-(5-chloro-3-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-3-[(1S)-1-(3,5-difluorophenyl)propyl]-6-hydroxy-3,4-dihydropyrimidin-4-one    (341),-   2-butyl-5-[3-(5-chloro-3-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-3-[(1S)-1-(3,5-difluorophenyl)propyl]-6-hydroxy-3,4-dihydropyrimidin-4-one    (342),-   2-butyl-5-[3-(3,5-difluoropyridin-2-yl)pyrrolidine-1-carbonyl]-6-hydroxy-3-[(1S)-1-phenylpropyl]-3,4-dihydropyrimidin-4-one    (343),-   2-butyl-5-[3-(5-chloro-3-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-6-hydroxy-3-[(1S)-1-phenylpropyl]-3,4-dihydropyrimidin-4-one    (344),-   2-butyl-5-[3-(3,5-difluoropyridin-2-yl)pyrrolidine-1-carbonyl]-6-hydroxy-3-[(1S)-1-phenylpropyl]-3,4-dihydropyrimidin-4-one    (345),-   2-butyl-5-[3-(5-chloro-3-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-6-hydroxy-3-[(1S)-1-phenylpropyl]-3,4-dihydropyrimidin-4-one    (346),-   2-butyl-3-[(1S)-1-(3,5-difluorophenyl)propyl]-5-[3-(3,5-difluoropyridin-2-yl)pyrrolidine-1-carbonyl]-6-hydroxy-3,4-dihydropyrimidin-4-one    (347),-   2-butyl-3-[(1S)-1-(3,5-difluorophenyl)propyl]-5-[3-(3,5-difluoropyridin-2-yl)pyrrolidine-1-carbonyl]-6-hydroxy-3,4-dihydropyrimidin-4-one    (348),-   2-butyl-5-[3-(3,5-difluoropyridin-2-yl)pyrrolidine-1-carbonyl]-6-hydroxy-3-[(1R)-2-methoxy-1-phenylethyl]-3,4-dihydropyrimidin-4-one    (349),-   2-butyl-5-[3-(5-chloro-3-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-6-hydroxy-3-[(1R)-2-methoxy-1-phenylethyl]-3,4-dihydropyrimidin-4-one    (350),-   3-[(S)-{2-butyl-5-[3-(3,5-difluoropyridin-2-yl)pyrrolidine-1-carbonyl]-4-hydroxy-6-oxo-1,6-dihydropyrimidin-1-yl}(cyclopropyl)methyl]benzonitrile    (351),-   2-butyl-5-[3-(5-chloro-3-fluoropyridin-2-yl)pyrrolidine-1-carbonyl]-6-hydroxy-3-[(1R)-2-methoxy-1-phenylethyl]-3,4-dihydropyrimidin-4-one    (352),-   5-[3-(2,6-difluorophenyl)pyrrolidine-1-carbonyl]-1-(2,6-dimethoxyphenyl)-2-(ethoxymethyl)-6-hydroxy-1,4-dihydropyrimidin-4-one    (353),-   5-[3-(2,6-difluorophenyl)pyrrolidine-1-carbonyl]-1-(2,6-dimethoxyphenyl)-2-(ethoxymethyl)-6-hydroxy-1,4-dihydropyrimidin-4-one    (354),-   2-butyl-5-(4-(2,3-dichlorobenzyl)piperazine-1-carbonyl)-1-(2,6-dimethoxyphenyl)-6-hydroxypyrimidin-4(1H)-one0.011    (355),-   2-butyl-5-(3-(5-chloro-3-fluoropyridin-2-yl)pyrrolidine-1-carbonyl)-1-(2,6-dimethoxyphenyl)-6-hydroxypyrimidin-4(1H)-one    (356),-   2-butyl-5-(3-(5-chloro-3-fluoropyridin-2-yl)pyrrolidine-1-carbonyl)-1-(2,6-dimethoxyphenyl)-6-hydroxypyrimidin-4(1H)-one    (357),-   2-butyl-5-(3-(3,5-difluoropyridin-2-yl)pyrrolidine-1-carbonyl)-1-(2,6-dimethoxyphenyl)-6-hydroxypyrimidin-4(1H)-one    (358),-   2-butyl-5-(3-(3,5-difluoropyridin-2-yl)pyrrolidine-1-carbonyl)-1-(2,6-dimethoxyphenyl)-6-hydroxypyrimidin-4(1H)-one    (359),-   5-(3-(2,4-difluorophenyl)pyrrolidine-1-carbonyl)-1-(2,6-dimethoxyphenyl)-2-(ethoxymethyl)-6-hydroxypyrimidin-4(1H)-one    (360),-   5-(3-(2,4-difluorophenyl)pyrrolidine-1-carbonyl)-1-(2,6-dimethoxyphenyl)-2-(ethoxymethyl)-6-hydroxypyrimidin-4(1H)-one    (361),-   2-(1-(1-(2,6-dimethoxyphenyl)-2-(ethoxymethyl)-6-hydroxy-4-oxo-1,4-dihydropyrimidine-5-carbonyl)pyrrolidin-3-yl)benzonitrile    (362),-   2-(1-(1-(2,6-dimethoxyphenyl)-2-(ethoxymethyl)-6-hydroxy-4-oxo-1,4-dihydropyrimidine-5-carbonyl)pyrrolidin-3-yl)benzonitrile    (363),-   2-(1-(2-butyl-1-(2,6-dimethoxyphenyl)-6-hydroxy-4-oxo-1,4-dihydropyrimidine-5-carbonyl)pyrrolidin-3-yl)benzonitrile    (364),-   2-(1-(2-butyl-1-(2,6-dimethoxyphenyl)-6-hydroxy-4-oxo-1,4-dihydropyrimidine-5-carbonyl)pyrrolidin-3-yl)benzonitrile    (365),-   2-butyl-1-(2,    6-dimethoxyphenyl)-5-(3-(3-fluoropyridin-2-yl)pyrrolidine-1-carbonyl)-6-hydroxypyrimidin-4(1H)-one    (366),-   2-butyl-1-(2,    6-dimethoxyphenyl)-5-(3-(3-fluoropyridin-2-yl)pyrrolidine-1-carbonyl)-6-hydroxypyrimidin-4(1H)-one    (367),-   2-(1-(2-(tert-butoxymethyl)-1-(2,6-dimethoxyphenyl)-6-hydroxy-4-oxo-1,4-dihydropyrimidine-5-carbonyl)pyrrolidin-3-yl)benzonitrile    (368),-   2-(1-(2-(tert-butoxymethyl)-1-(2,6-dimethoxyphenyl)-6-hydroxy-4-oxo-1,4-dihydropyrimidine-5-carbonyl)pyrrolidin-3-yl)benzonitrile    (369),-   2-butyl-1-(2,    6-dimethoxyphenyl)-5-(3-(5-fluoropyridin-2-yl)pyrrolidine-1-carbonyl)-6-hydroxypyrimidin-4(1H)-one    (370),-   2-butyl-1-(2,    6-dimethoxyphenyl)-5-(3-(5-fluoropyridin-2-yl)pyrrolidine-1-carbonyl)-6-hydroxypyrimidin-4(1H)-one    (371),-   5-(3-(3,5-difluoropyridin-2-yl)pyrrolidine-1-carbonyl)-1-(2,6-dimethoxyphenyl)-2-(ethoxymethyl)-6-hydroxypyrimidin-4(1H)-one    (372),-   2-butyl-5-(4-(4-chlorophenoxy)piperidine-1-carbonyl)-1-(2,6-dimethoxyphenyl)-6-hydroxypyrimidin-4(1H)-one    (373),-   1-(2,6-dimethoxyphenyl)-2-(ethoxymethyl)-5-(4-(4-fluorobenzyl)piperidine-1-carbonyl)-6-hydroxypyrimidin-4(1H)-one    (374),-   5-(4-(4-chlorobenzyl)piperidine-1-carbonyl)-1-(2,6-dimethoxyphenyl)-2-(ethoxymethyl)-6-hydroxypyrimidin-4(1H)-one    (375),-   (S)-5-(3-(benzyloxy)pyrrolidine-1-carbonyl)-1-(2,6-dimethoxyphenyl)-2-(ethoxymethyl)-6-hydroxypyrimidin-4(1H)-one    (376),-   5-(4-(4-chlorophenoxy)piperidine-1-carbonyl)-1-(2,6-dimethoxyphenyl)-2-(ethoxymethyl)-6-hydroxypyrimidin-4(1H)-one    (377),-   5-(4-(2-chloro-5-fluorophenoxy)piperidine-1-carbonyl)-1-(2,6-dimethoxyphenyl)-2-(ethoxymethyl)-6-hydroxypyrimidin-4(1H)-one    (378),-   1-(2,6-dimethoxyphenyl)-2-(ethoxymethyl)-5-(4-(2-fluorophenyl)piperidine-1-carbonyl)-6-hydroxypyrimidin-4(1H)-one    (379),-   2-butyl-1-(2,6-dimethoxyphenyl)-6-hydroxy-5-(4-(4-(trifluoromethyl)benzyl)piperidine-1-carbonyl)pyrimidin-4(1H)-one    (380),-   2-butyl-5-(4-(4-(tert-butyl)phenoxy)piperidine-1-carbonyl)-1-(2,6-dimethoxyphenyl)-6-hydroxypyrimidin-4(1H)-one    (381),-   2-butyl-5-(4-(2-chlorophenoxy)piperidine-1-carbonyl)-1-(2,6-dimethoxyphenyl)-6-hydroxypyrimidin-4(1H)-one    (382),-   2-butyl-5-(4-(2-chloro-3-fluorophenoxy)piperidine-1-carbonyl)-1-(2,6-dimethoxyphenyl)-6-hydroxypyrimidin-4(1H)-one    (383),-   2-butyl-5-(4-(2-chloro-3-fluorophenoxy)piperidine-1-carbonyl)-1-(2,6-dimethoxyphenyl)-6-hydroxypyrimidin-4(1H)-one    (384),-   2-butyl-5-(4-(2-chloro-5-fluorophenoxy)piperidine-1-carbonyl)-1-(2,6-dimethoxyphenyl)-6-hydroxypyrimidin-4(1H)-one    (385),-   2-butyl-5-(4-(2-chloro-3,5-difluorophenoxy)piperidine-1-carbonyl)-1-(2,6-dimethoxyphenyl)-6-hydroxypyrimidin-4(1H)-one    (386),-   2-butyl-5-(4-(2,3-difluorophenoxy)piperidine-1-carbonyl)-1-(2,6-dimethoxyphenyl)-6-hydroxypyrimidin-4(1H)-one    (387),-   2-butyl-5-(4-(2,3-difluorobenzyl)piperazine-1-carbonyl)-1-(2,6-dimethoxyphenyl)-6-hydroxypyrimidin-4(1H)-one    (388).

The invention may be embodied in other specific forms without departingfrom the spirit or essential attributes thereof. This invention alsoencompasses all combinations of alternative aspects of the inventionnoted herein. It is understood that any and all embodiments of thepresent invention may be taken in conjunction with any other embodimentto describe additional embodiments of the present invention.Furthermore, any elements (including individual variable definitions) ofan embodiment are meant to be combined with any and all other elementsfrom any of the embodiments to describe additional embodiments. Thepresent invention also provides a pharmaceutical composition comprisinga compound of formula I, or an enantiomer, diastereomer, or apharmaceutically-acceptable salt, and a pharmaceutically acceptablecarrier therefore.

In another embodiment, the compounds of the present invention have EC₅₀values≦10 μM, using the APJ hcAMP assay disclosed herein, preferably,EC₅₀ values<5 μM, more preferably, EC₅₀ values<1 μM, even morepreferably, EC₅₀ values<0.5 μM, even more preferably, EC₅₀ values<0.1μM, even more preferably, EC₅₀ values<0.01 μM.

In another aspect, the present invention provides compounds selectedfrom any subset list of compounds exemplified in the presentapplication.

In another aspect, the present invention provides compounds selectedfrom the subset in which the APJ hcAMP EC₅₀ potency range is A.

In another aspect, the present invention provides compounds selectedfrom the subset in which the APJ hcAMP EC₅₀ potency range is B.

In another aspect, the present invention provides compounds selectedfrom the subset in which the APJ hcAMP EC₅₀ potency range is C.

II. Other Embodiments of the Invention

In another embodiment, the present invention provides a compositioncomprising at least one of the compounds of the present invention or astereoisomer, a tautomer, a pharmaceutically acceptable salt, or asolvate thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and atleast one of the compounds of the present invention or a stereoisomer, atautomer, a pharmaceutically acceptable salt, or a solvate thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition, comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of at least one of the compounds of thepresent invention or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof.

In another embodiment, the present invention provides a process formaking a compound of the present invention or a stereoisomer, atautomer, a pharmaceutically acceptable salt, or a solvate thereof.

In another embodiment, the present invention provides an intermediatefor making a compound of the present invention or a stereoisomer, atautomer, a pharmaceutically acceptable salt, or a solvate thereof.

The present invention provides a pharmaceutical composition furthercomprising additional therapeutic agent(s). In a preferred embodiment,the present invention provides pharmaceutical composition, wherein theadditional therapeutic agent is, for example, angiotensin convertingenzyme (ACE) inhibitor, β-adrenergic receptor blocker, angiotensin IIreceptor blocker, diuretic, aldosterone antagonist and digitaliscompound.

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of multiple diseases or disordersassociated with APJ or apelin activity, comprising administering to apatient in need of such treatment and/or prophylaxis a therapeuticallyeffective amount of at least one of the compounds of the presentinvention, alone, or, optionally, in combination with another compoundof the present invention and/or at least one other type of therapeuticagent.

Examples of diseases or disorders associated with the activity of theAPJ and apelin that can be prevented, modulated, or treated according tothe present invention include, but are not limited to heart failure suchas acute decompensated heart failure (ADHF), atrial fibrillation,coronary artery disease, peripheral vascular disease, atherosclerosis,diabetes, metabolic syndrome, hypertension, pulmonary hypertension,cerebrovascular disorders and the sequelae thereof, cardiovasculardisorders, angina, ischemia, stroke, myocardial infarction, acutecoronary syndrome, reperfusion injury, angioplastic restenosis, vascularcomplications of diabetes and obesity.

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of heart failure, coronary artery disease,peripheral vascular disease, atherosclerosis, diabetes, metabolicsyndrome, hypertension, pulmonary hypertension, atrial fibrillation,angina, ischemia, stroke, myocardial infarction, acute coronarysyndrome, reperfusion injury, angioplastic restenosis, vascularcomplications of diabetes, obesity, comprising administering to apatient in need of such treatment and/or prophylaxis a therapeuticallyeffective amount of at least one of the compounds of the presentinvention, alone, or, optionally, in combination with another compoundof the present invention and/or at least one other type of therapeuticagent.

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of heart failure such as ADHF, comprisingadministering to a patient in need of such treatment and/or prophylaxisa therapeutically effective amount of at least one of the compounds ofthe present invention, alone, or, optionally, in combination withanother compound of the present invention and/or at least one other typeof therapeutic agent.

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of diabetes and obesity, comprisingadministering to a patient in need of such treatment and/or prophylaxisa therapeutically effective amount of at least one of the compounds ofthe present invention, alone, or, optionally, in combination withanother compound of the present invention and/or at least one other typeof therapeutic agent.

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of hypertension, comprising administeringto a patient in need of such treatment and/or prophylaxis atherapeutically effective amount of at least one of the compounds of thepresent invention, alone, or, optionally, in combination with anothercompound of the present invention and/or at least one other type oftherapeutic agent.

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of pulmonary hypertension, comprisingadministering to a patient in need of such treatment and/or prophylaxisa therapeutically effective amount of at least one of the compounds ofthe present invention, alone, or, optionally, in combination withanother compound of the present invention and/or at least one other typeof therapeutic agent.

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of acute coronary syndrome and cardiacischemia, comprising administering to a patient in need of suchtreatment and/or prophylaxis a therapeutically effective amount of atleast one of the compounds of the present invention, alone, or,optionally, in combination with another compound of the presentinvention and/or at least one other type of therapeutic agent.

In another embodiment, the present invention provides a compound of thepresent invention for use in therapy.

In another embodiment, the present invention provides a compound of thepresent invention for use in therapy for the treatment and/orprophylaxis of multiple diseases or disorders associated with APJ andapelin.

In another embodiment, the present invention also provides the use of acompound of the present invention for the manufacture of a medicamentfor the treatment and/or prophylaxis of multiple diseases or disordersassociated with APJ and apelin.

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of multiple diseases or disordersassociated with APJ and apelin, comprising administering to a patient inneed thereof a therapeutically effective amount of a first and secondtherapeutic agent, wherein the first therapeutic agent is a compound ofthe present invention. Preferably, the second therapeutic agent, forexample selected inotropic agent such as β-adrenergic agonist (forexample dobutamine).

In another embodiment, the present invention provides a combinedpreparation of a compound of the present invention and additionaltherapeutic agent(s) for simultaneous, separate or sequential use intherapy.

In another embodiment, the present invention provides a combinedpreparation of a compound of the present invention and additionaltherapeutic agent(s) for simultaneous, separate or sequential use in thetreatment and/or prophylaxis of multiple diseases or disordersassociated with APJ and apelin.

Where desired, the compound of the present invention may be used incombination with one or more other types of cardiovascular agents and/orone or more other types of therapeutic agents which may be administeredorally in the same dosage form, in a separate oral dosage form or byinjection. The other type of cardiovascular agents that may beoptionally employed in combination with the APJ agonist of the presentinvention may be one, two, three or more cardiovascular agentsadministered orally in the same dosage form, in a separate oral dosageform, or by injection to produce an additional pharmacological benefit.

The compounds of the present invention may be employed in combinationwith additional therapeutic agent(s) selected from one or more,preferably one to three, of the following therapeutic agents:anti-hypertensive agents, ACE inhibitors, mineralocorticoid receptorantagonists, angiotensin receptor blockers, calcium channel blockers,β-adrenergic receptor blockers, diuretics, vasorelaxation agents such asnitrates, anti-atherosclerotic agents, anti-dyslipidemic agents,anti-diabetic agents, anti-hyperglycemic agents, anti-hyperinsulinemicagents, anti-thrombotic agents, anti-retinopathic agents,anti-neuropathic agents, anti-nephropathic agents, anti-ischemic agents,calcium channel blockers, anti-obesity agents, anti-hyperlipidemicagents, anti-hypertriglyceridemic agents, anti-hypercholesterolemicagents, anti-restenotic agents, anti-pancreatic agents, lipid loweringagents, anorectic agents, memory enhancing agents, anti-dementia agents,cognition promoting agents, appetite suppressants, agents for treatingheart failure, agents for treating peripheral arterial disease, agentsfor treating malignant tumors, and anti-inflammatory agents.

In another embodiment, additional therapeutic agent(s) used in combinedpharmaceutical compositions or combined methods or combined uses, areselected from one or more, preferably one to three, of the followingtherapeutic agents in treating heart failure: ACE inhibitors,β-blockers, diuretics, mineralocorticoid receptor antagonists, renininhibitors, calcium channel blockers, angiotensin II receptorantagonists, nitrates, digitalis compounds, inotropic agents.

The present invention may be embodied in other specific forms withoutparting from the spirit or essential attributes thereof. This inventionencompasses all combinations of preferred aspects of the invention notedherein. It is understood that any and all embodiments of the presentinvention may be taken in conjunction with any other embodiment orembodiments to describe additional embodiments. It is also understoodthat each individual element of the embodiments is its own independentembodiment. Furthermore, any element of an embodiment is meant to becombined with any and all other elements from any embodiment to describean additional embodiment.

III. Chemistry

Throughout the specification and the appended claims, a given chemicalformula or name shall encompass all stereo and optical isomers andracemates thereof where such isomers exist. Unless otherwise indicated,all chiral (enantiomeric and diastereomeric) and racemic forms arewithin the scope of the invention. Many geometric isomers of C═C doublebonds, C═N double bonds, ring systems, and the like can also be presentin the compounds, and all such stable isomers are contemplated in thepresent invention. Cis- and trans- (or E- and Z-) geometric isomers ofthe compounds of the present invention are described and may be isolatedas a mixture of isomers or as separated isomeric forms. The presentcompounds can be isolated in optically active or racemic forms.Optically active forms may be prepared by resolution of racemic forms orby synthesis from optically active starting materials. All processesused to prepare compounds of the present invention and intermediatesmade therein are considered to be part of the present invention. Whenenantiomeric or diastereomeric products are prepared, they may beseparated by conventional methods, for example, by chromatography orfractional crystallization. Depending on the process conditions the endproducts of the present invention are obtained either in free (neutral)or salt form. Both the free form and the salts of these end products arewithin the scope of the invention. If so desired, one form of a compoundmay be converted into another form. A free base or acid may be convertedinto a salt; a salt may be converted into the free compound or anothersalt; a mixture of isomeric compounds of the present invention may beseparated into the individual isomers. Compounds of the presentinvention, free form and salts thereof, may exist in multiple tautomericforms, in which hydrogen atoms are transposed to other parts of themolecules and the chemical bonds between the atoms of the molecules areconsequently rearranged. It should be understood that all tautomericforms, insofar as they may exist, are included within the invention.

As used herein, the term “alkyl” or “alkylene” is intended to includeboth branched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms. For examples, “C₁ to C₁₂alkyl” or “C₁₋₁₂ alkyl” (or alkylene), is intended to include C₁, C₂,C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁ and C₁₂ alkyl groups; “C₄ to Cisalkyl” or “C₄₋₁₈ alkyl” (or alkylene), is intended to include C₄, C₅,C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃, C₁₄, C₁₅, C₁₆, C₁₇, and Cis alkylgroups. Additionally, for example, “C₁ to C₆ alkyl” or “C₁₋₆ alkyl”denotes alkyl having 1 to 6 carbon atoms. Alkyl group can beunsubstituted or substituted with at least one hydrogen being replacedby another chemical group. Example alkyl groups include, but are notlimited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl andisopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), and pentyl (e.g.,n-pentyl, isopentyl, neopentyl). When “C₀ alkyl” or “C₀ alkylene” isused, it is intended to denote a direct bond.

“Alkenyl” or “alkenylene” is intended to include hydrocarbon chains ofeither straight or branched configuration having the specified number ofcarbon atoms and one or more, preferably one to two, carbon-carbondouble bonds that may occur in any stable point along the chain. Forexample, “C₂ to C₆ alkenyl” or “C₂₋₆ alkenyl” (or alkenylene), isintended to include C₂, C₃, C₄, C₅, and C₆ alkenyl groups. Examples ofalkenyl include, but are not limited to, ethenyl, 1-propenyl,2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3, pentenyl, 4-pentenyl,2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and4-methyl-3-pentenyl.

“Alkynyl” or “alkynylene” is intended to include hydrocarbon chains ofeither straight or branched configuration having one or more, preferablyone to three, carbon-carbon triple bonds that may occur in any stablepoint along the chain. For example, “C₂ to C₆ alkynyl” or “C₂₋₆ alkynyl”(or alkynylene), is intended to include C₂, C₃, C₄, C₅, and C₆ alkynylgroups; such as ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

When the term “hydrocarbon chain” is used, it is intended to include“alkyl”, “alkenyl” and “alkynyl”, unless otherwise specified.

The term “alkoxy” or “alkyloxy” refers to an —O-alkyl group. Forexample, “C₁ to C₆ alkoxy” or “C₁₋₆ alkoxy” (or alkyloxy), is intendedto include C₁, C₂, C₃, C₄, C₅, and C₆ alkoxy groups. Example alkoxygroups include, but are not limited to, methoxy, ethoxy, propoxy (e.g.,n-propoxy and isopropoxy), and t-butoxy. Similarly, “alkylthio” or“thioalkoxy” represents an alkyl group as defined above with theindicated number of carbon atoms attached through a sulphur bridge; forexample methyl-S— and ethyl-S—.

“Halo” or “halogen” includes fluoro, chloro, bromo, and iodo.“Haloalkyl” is intended to include both branched and straight-chainsaturated aliphatic hydrocarbon groups having the specified number ofcarbon atoms, substituted with 1 or more halogens. Examples of haloalkylinclude, but are not limited to, fluoromethyl, difluoromethyl,trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl,2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examplesof haloalkyl also include “fluoroalkyl” that is intended to include bothbranched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms, substituted with 1 or morefluorine atoms.

“Haloalkoxy” or “haloalkyloxy” represents a haloalkyl group as definedabove with the indicated number of carbon atoms attached through anoxygen bridge. For example, “C₁₋₆ haloalkoxy”, is intended to includeC₁, C₂, C₃, C₄, C₅, and C₆ haloalkoxy groups. Examples of haloalkoxyinclude, but are not limited to, trifluoromethoxy,2,2,2-trifluoroethoxy, and pentafluorothoxy. Similarly, “haloalkylthio”or “thiohaloalkoxy” represents a haloalkyl group as defined above withthe indicated number of carbon atoms attached through a sulphur bridge;for example trifluoromethyl-S—, and pentafluoroethyl-S—.

The term “cycloalkyl” refers to cyclized alkyl groups, including mono-,bi- or poly-cyclic ring systems. For example, “C₃ to C₆ cycloalkyl” or“C₃₋₆ cycloalkyl” is intended to include C₃, C₄, C₅, and C₆ cycloalkylgroups. Example cycloalkyl groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbomyl. Branchedcycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropylare included in the definition of “cycloalkyl”. The term “cycloalkenyl”refers to cyclized alkenyl groups. C₄₋₆ cycloalkenyl is intended toinclude C₄, C₅, and C₆ cycloalkenyl groups. Example cycloalkenyl groupsinclude, but are not limited to, cyclobutenyl, cyclopentenyl, andcyclohexenyl.

As used herein, “carbocycle”, “carbocyclyl”, or “carbocyclic residue” isintended to mean any stable 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclicor bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, or 13-membered bicyclic ortricyclic hydrocarbon ring, any of which may be saturated, partiallyunsaturated, unsaturated or aromatic. Examples of such carbocyclesinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl,cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl,cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl,[3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane(decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl,adamantyl, anthracenyl, and tetrahydronaphthyl (tetralin). As shownabove, bridged rings are also included in the definition of carbocycle(e.g., [2.2.2]bicyclooctane). Preferred carbocycles, unless otherwisespecified, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,indanyl, and tetrahydronaphthyl. When the term “carbocycle” is used, itis intended to include “aryl.” A bridged ring occurs when one or more,preferably one to three, carbon atoms link two non-adjacent carbonatoms. Preferred bridges are one or two carbon atoms. It is noted that abridge always converts a monocyclic ring into a tricyclic ring. When aring is bridged, the substituents recited for the ring may also bepresent on the bridge.

As used herein, the term “bicyclic carbocycle” or “bicyclic carbocyclicgroup” is intended to mean a stable 9- or 10-membered carbocyclic ringsystem that contains two fused rings and consists of carbon atoms. Ofthe two fused rings, one ring is a benzo ring fused to a second ring;and the second ring is a 5- or 6-membered carbon ring which issaturated, partially unsaturated, or unsaturated. The bicycliccarbocyclic group may be attached to its pendant group at any carbonatom which results in a stable structure. The bicyclic carbocyclic groupdescribed herein may be substituted on any carbon if the resultingcompound is stable. Examples of a bicyclic carbocyclic group are, butnot limited to, naphthyl, 1,2-dihydronaphthyl,1,2,3,4-tetrahydronaphthyl, and indanyl.

“Aryl” groups refer to monocyclic or bicyclic aromatic hydrocarbons,including, for example, phenyl, and naphthyl. Aryl moieties are wellknown and described, for example, in Lewis, R. J., ed., Hawley'sCondensed Chemical Dictionary, 15th Edition, John Wiley & Sons, Inc.,New York (2007). “C₆₋₁₀ aryl” refers to phenyl and naphthyl.

The term “benzyl”, as used herein, refers to a methyl group on which oneof the hydrogen atoms is replaced by a phenyl group.

As used herein, the term “heterocycle”, “heterocyclyl”, or “heterocyclicgroup” is intended to mean a stable 3-, 4-, 5-, 6-, or 7-memberedmonocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-memberedpolycyclic heterocyclic ring that is saturated, partially unsaturated,or fully unsaturated, and that contains carbon atoms and 1, 2, 3 or 4heteroatoms independently selected from the group consisting of N, O andS; and including any polycyclic group in which any of the above-definedheterocyclic rings is fused to a benzene ring. The nitrogen and sulfurheteroatoms may optionally be oxidized (i.e., N→O and S(O)_(p), whereinp is 0, 1 or 2). The nitrogen atom may be substituted or unsubstituted(i.e., N or NR wherein R is H or another substituent, if defined). Theheterocyclic ring may be attached to its pendant group at any heteroatomor carbon atom that results in a stable structure. The heterocyclicrings described herein may be substituted on carbon or on a nitrogenatom if the resulting compound is stable. A nitrogen in the heterocyclemay optionally be quaternized. It is preferred that when the totalnumber of S and O atoms in the heterocycle exceeds 1, then theseheteroatoms are not adjacent to one another. It is preferred that thetotal number of S and O atoms in the heterocycle is not more than 1.When the term “heterocycle” is used, it is intended to includeheteroaryl.

Examples of heterocycles include, but are not limited to, acridinyl,azetidinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, imidazolopyridinyl, indolenyl,indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl,methylenedioxyphenyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolopyridinyl, oxazolidinylperimidinyl, oxindolyl,pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl,pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl,pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl,pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl,2-pyrrolidonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl,4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrazolyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thiazolopyridinyl, thienothiazolyl, thienooxazolyl,thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Alsoincluded are fused ring and spiro compounds containing, for example, theabove heterocycles.

Examples of 5- to 10-membered heterocycles include, but are not limitedto, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl,piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl,tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl,oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl,triazinyl, triazolyl, benzimidazolyl, 1H-indazolyl, benzofuranyl,benzothiofuranyl, benztetrazolyl, benzotriazolyl, benzisoxazolyl,benzoxazolyl, oxindolyl, benzoxazolinyl, benzthiazolyl,benzisothiazolyl, isatinoyl, isoquinolinyl, octahydroisoquinolinyl,tetrahydroisoquinolinyl, tetrahydroquinolinyl, isoxazolopyridinyl,quinazolinyl, quinolinyl, isothiazolopyridinyl, thiazolopyridinyl,oxazolopyridinyl, imidazolopyridinyl, and pyrazolopyridinyl.

Examples of 5- to 6-membered heterocycles include, but are not limitedto, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl,piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl,tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl,oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl,triazinyl, and triazolyl. Also included are fused ring and spirocompounds containing, for example, the above heterocycles.

As used herein, the term “bicyclic heterocycle” or “bicyclicheterocyclic group” is intended to mean a stable 9- or 10-memberedheterocyclic ring system which contains two fused rings and consists ofcarbon atoms and 1, 2, 3, or 4 heteroatoms independently selected fromthe group consisting of N, O and S. Of the two fused rings, one ring isa 5- or 6-membered monocyclic aromatic ring comprising a 5-memberedheteroaryl ring, a 6-membered heteroaryl ring or a benzo ring, eachfused to a second ring. The second ring is a 5- or 6-membered monocyclicring which is saturated, partially unsaturated, or unsaturated, andcomprises a 5-membered heterocycle, a 6-membered heterocycle or acarbocycle (provided the first ring is not benzo when the second ring isa carbocycle).

The bicyclic heterocyclic group may be attached to its pendant group atany heteroatom or carbon atom which results in a stable structure. Thebicyclic heterocyclic group described herein may be substituted oncarbon or on a nitrogen atom if the resulting compound is stable. It ispreferred that when the total number of S and O atoms in the heterocycleexceeds 1, then these heteroatoms are not adjacent to one another. It ispreferred that the total number of S and O atoms in the heterocycle isnot more than 1.

Examples of a bicyclic heterocyclic group are, but not limited to,quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl,isoindolyl, indolinyl, 1H-indazolyl, benzimidazolyl,1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,5,6,7,8-tetrahydro-quinolinyl, 2,3-dihydro-benzofuranyl, chromanyl,1,2,3,4-tetrahydro-quinoxalinyl, and 1,2,3,4-tetrahydro-quinazolinyl.

As used herein, the term “aromatic heterocyclic group” or “heteroaryl”is intended to mean stable monocyclic and polycyclic aromatichydrocarbons that include at least one heteroatom ring member such assulfur, oxygen, or nitrogen. Heteroaryl groups include, withoutlimitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl,pyrroyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl,pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl,isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl,benzodioxolanyl, and benzodioxane. Heteroaryl groups are substituted orunsubstituted. The nitrogen atom is substituted or unsubstituted (i.e.,N or NR wherein R is H or another substituent, if defined). The nitrogenand sulfur heteroatoms may optionally be oxidized (i.e., N→O andS(O)_(p), wherein p is 0, 1 or 2).

Examples of 5- to 6-membered heteroaryls include, but are not limitedto, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl,imidazolyl, imidazolidinyl, tetrazolyl, isoxazolyl, oxazolyl,oxadiazolyl, oxazolidinyl, thiadiazinyl, thiadiazolyl, thiazolyl,triazinyl, and triazolyl.

Bridged rings are also included in the definition of heterocycle. Abridged ring occurs when one or more, preferably one to three, atoms(i.e., C, O, N, or S) link two non-adjacent carbon or nitrogen atoms.Examples of bridged rings include, but are not limited to, one carbonatom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and acarbon-nitrogen group. It is noted that a bridge always converts amonocyclic ring into a tricyclic ring. When a ring is bridged, thesubstituents recited for the ring may also be present on the bridge.

The term “counter ion” is used to represent a negatively charged speciessuch as chloride, bromide, hydroxide, acetate, and sulfate or apositively charged species such as sodium (Na+), potassium (K+),ammonium (R_(n)NH_(m)+ where n=0-4 and m=0-4) and the like.

When a dotted ring is used within a ring structure, this indicates thatthe ring structure may be saturated, partially saturated or unsaturated.

As used herein, the term “amine protecting group” means any group knownin the art of organic synthesis for the protection of amine groups whichis stable to an ester reducing agent, a disubstituted hydrazine, R4-Mand R7-M, a nucleophile, a hydrazine reducing agent, an activator, astrong base, a hindered amine base and a cyclizing agent. Such amineprotecting groups fitting these criteria include those listed in Wuts,P. G. M. et al., Protecting Groups in Organic Synthesis, 4th Edition,Wiley (2007) and The Peptides: Analysis, Synthesis, Biology, Vol. 3,Academic Press, New York (1981), the disclosure of which is herebyincorporated by reference. Examples of amine protecting groups include,but are not limited to, the following: (1) acyl types such as formyl,trifluoroacetyl, phthalyl, and p-toluenesulfonyl; (2) aromatic carbamatetypes such as benzyloxycarbonyl (Cbz) and substitutedbenzyloxycarbonyls, 1-(p-biphenyl)-1-methylethoxycarbonyl, and9-fluorenylmethyloxycarbonyl (Fmoc); (3) aliphatic carbamate types suchas tert-butyloxycarbonyl (Boc), ethoxycarbonyl,diisopropylmethoxycarbonyl, and allyloxycarbonyl; (4) cyclic alkylcarbamate types such as cyclopentyloxycarbonyl and adamantyloxycarbonyl;(5) alkyl types such as triphenylmethyl and benzyl; (6) trialkylsilanesuch as trimethylsilane; (7) thiol containing types such asphenylthiocarbonyl and dithiasuccinoyl; and (8) alkyl types such astriphenylmethyl, methyl, and benzyl; and substituted alkyl types such as2,2,2-trichloroethyl, 2-phenylethyl, and t-butyl; and trialkylsilanetypes such as trimethylsilane.

As referred to herein, the term “substituted” means that at least onehydrogen atom is replaced with a non-hydrogen group, provided thatnormal valencies are maintained and that the substitution results in astable compound. Ring double bonds, as used herein, are double bondsthat are formed between two adjacent ring atoms (e.g., C═C, C═N, orN═N).

In cases wherein there are nitrogen atoms (e.g., amines) on compounds ofthe present invention, these may be converted to N-oxides by treatmentwith an oxidizing agent (e.g., mCPBA and/or hydrogen peroxides) toafford other compounds of this invention. Thus, shown and claimednitrogen atoms are considered to cover both the shown nitrogen and itsN-oxide (N→O) derivative.

When any variable occurs more than one time in any constituent orformula for a compound, its definition at each occurrence is independentof its definition at every other occurrence. Thus, for example, if agroup is shown to be substituted with 0-3 R, then said group mayoptionally be substituted with up to three R groups, and at eachoccurrence R is selected independently from the definition of R.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom in whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent.

Combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms that are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, and/or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic groups such as amines; and alkali or organic saltsof acidic groups such as carboxylic acids. The pharmaceuticallyacceptable salts include the conventional non-toxic salts or thequaternary ammonium salts of the parent compound formed, for example,from non-toxic inorganic or organic acids. For example, suchconventional non-toxic salts include those derived from inorganic acidssuch as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, andnitric; and the salts prepared from organic acids such as acetic,propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric,ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, andisethionic, and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound that contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Allen, Jr., L. V.,ed., Remington: The Science andPractice of Pharmacy, 22nd Edition,Pharmaceutical Press, London, UK (2012), the disclosure of which ishereby incorporated by reference.

In addition, compounds of formula I may have prodrug forms. Any compoundthat will be converted in vivo to provide the bioactive agent (i.e., acompound of formula I) is a prodrug within the scope and spirit of theinvention. Various forms of prodrugs are well known in the art. Forexamples of such prodrug derivatives, see:

-   a) Bundgaard, H., ed., Design of Prodrugs, Elsevier (1985), and    Widder, K. et al., eds., Methods in Enzymology, 112:309-396,    Academic Press (1985);-   b) Bundgaard, H., Chapter 5, “Design and Application of Prodrugs”,    Krosgaard-Larsen, P. et al., eds., A Textbook of Drug Design and    Development, pp. 113-191, Harwood Academic Publishers (1991);-   c) Bundgaard, H., Adv. Drug Deliv. Rev., 8:1-38 (1992);-   d) Bundgaard, H. et al., J. Pharm. Sci., 77:285 (1988);-   e) Kakeya, N. et al., Chem. Pharm. Bull., 32:692 (1984); and-   f) Rautio, J., ed., Prodrugs and Targeted Delivery (Methods and    Principles in Medicinal Chemistry), Vol. 47, Wiley-VCH (2011).

Compounds containing a carboxy group can form physiologicallyhydrolyzable esters that serve as prodrugs by being hydrolyzed in thebody to yield formula I compounds per se. Such prodrugs are preferablyadministered orally since hydrolysis in many instances occursprincipally under the influence of the digestive enzymes. Parenteraladministration may be used where the ester per se is active, or in thoseinstances where hydrolysis occurs in the blood. Examples ofphysiologically hydrolyzable esters of compounds of formula I includeC₁₋₆alkyl, C₁₋₆alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl,methoxymethyl, C₁₋₆ alkanoyloxy-C₁₋₆alkyl (e.g., acetoxymethyl,pivaloyloxymethyl or propionyloxymethyl),C₁₋₆alkoxycarbonyloxy-C₁₋₆alkyl (e.g., methoxycarbonyl-oxymethyl orethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl,(5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl), and other well-knownphysiologically hydrolyzable esters used, for example, in the penicillinand cephalosporin arts. Such esters may be prepared by conventionaltechniques known in the art.

Preparation of prodrugs is well known in the art and described in, forexample, King, F. D., ed., Medicinal Chemistry: Principles and Practice,The Royal Society of Chemistry, Cambridge, UK (2nd Edition, reproduced(2006)); Testa, B. et al., Hydrolysis in Drug and Prodrug Metabolism.Chemistry, Biochemistry and Enzymology, VCHA and Wiley-VCH, Zurich,Switzerland (2003); Wermuth, C. G., ed., The Practice ofMedicinalChemistry, 3rd Edition, Academic Press, San Diego, Calif. (2008).

The present invention is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include deuteriumand tritium. Deuterium has one proton and one neutron in its nucleus andthat has twice the mass of ordinary hydrogen. Deuterium can berepresented by symbols such as “²H” or “D”. The term “deuterated”herein, by itself or used to modify a compound or group, refers toreplacement of one or more hydrogen atom(s), which is attached tocarbon(s), with a deuterium atom. Isotopes of carbon include ¹³C and¹⁴C.

Isotopically-labeled compounds of the invention can generally beprepared by conventional techniques known to those skilled in the art orby processes analogous to those described herein, using an appropriateisotopically-labeled reagent in place of the non-labeled reagentotherwise employed. Such compounds have a variety of potential uses,e.g., as standards and reagents in determining the ability of apotential pharmaceutical compound to bind to target proteins orreceptors, or for imaging compounds of this invention bound tobiological receptors in vivo or in vitro.

The term “solvate” means a physical association of a compound of thisinvention with one or more solvent molecules, whether organic orinorganic. This physical association includes hydrogen bonding. Incertain instances the solvate will be capable of isolation, for examplewhen one or more solvent molecules are incorporated in the crystallattice of the crystalline solid. The solvent molecules in the solvatemay be present in a regular arrangement and/or a non-orderedarrangement. The solvate may comprise either a stoichiometric ornonstoichiometric amount of the solvent molecules. “Solvate” encompassesboth solution-phase and isolable solvates. Exemplary solvates include,but are not limited to, hydrates, ethanolates, methanolates, andisopropanolates. Methods of solvation are generally known in the art.

Abbreviations as used herein, are defined as follows: “1×” for once,“2×” for twice, “3×” for thrice, “° C.” for degrees Celsius, “eq” forequivalent or equivalents, “g” for gram or grams, “mg” for milligram ormilligrams, “L” for liter or liters, “mL” for milliliter or milliliters,“μL” for microliter or microliters, “N” for normal, “M” for molar,“mmol” for millimole or millimoles, “min” for minute or min, “h” forhour or h, “rt” for room temperature, “RT” for retention time, “atm” foratmosphere, “psi” for pounds per square inch, “conc.” for concentrate,“aq” for “aqueous”, “sat” or “sat'd” for saturated, “MW” for molecularweight, “mp” for melting point, “MS” or “Mass Spec” for massspectrometry, “ESI” for electrospray ionization mass spectroscopy, “HR”for high resolution, “HRMS” for high resolution mass spectrometry,“LCMS” for liquid chromatography mass spectrometry, “HPLC” for highpressure liquid chromatography, “RP HPLC” for reverse phase HPLC, “TLC”or “tlc” for thin layer chromatography, “NMR” for nuclear magneticresonance spectroscopy, “nOe” for nuclear Overhauser effectspectroscopy, “¹H” for proton, “δ” for delta, “s” for singlet, “d” fordoublet, “t” for triplet, “q” for quartet, “m” for multiplet, “br” forbroad, “Hz” for hertz, and “α”, “β”, “R”, “S”, “E”, “Z” and “ee” arestereochemical designations familiar to one skilled in the art.

-   AcOH or HOAc acetic acid-   ACN acetonitrile-   Alk Alkyl-   AlMe₃ Trimethylaluminum-   BBr₃ boron tribromide-   Bn benzyl-   Boc tert-butyloxycarbonyl-   BOP reagent benzotriazol-1-yloxytris(dimethylamino)phosphonium    hexafluorophosphate-   Bu butyl-   i-Bu isobutyl-   t-Bu tert-butyl-   t-BuOH tert-butanol-   Cbz carbobenzyloxy-   CDCl₃ deutero-chloroform-   CD₃OD deutero-methanol-   CH₂Cl₂ dichloromethane-   CH₃CN acetonitrile-   CHCl₃ chloroform-   DCM dichloromethane-   DIEA, DIPEA or Hunig's base diisopropylethylamine-   DMF dimethyl formamide-   DMSO dimethyl sulfoxide-   Et ethyl-   Et₃N or TEA triethylamine-   Et₂O diethyl ether-   EtOAc ethyl acetate-   EtOH ethanol-   HCl hydrochloric acid-   HPLC high-performance liquid chromatography-   K₂CO₃ potassium carbonate-   K₂HPO₄ potassium hydrogenphosphate-   LCMS liquid chromatography mass spectrometry-   LiHMDS lithium bis(trimethylsilyl)amide-   LG leaving group-   Me methyl-   MeOH methanol-   MgSO₄ magnesium sulfate-   MsOH or MSA methylsulfonic acid-   NaCl sodium chloride-   Na₂CO₃ sodium carbonate-   NaHCO₃ sodium bicarbonate-   NaOH sodium hydroxide-   Na₂SO₄ sodium sulfate-   NH₃ ammonia-   NH₄C₁ ammonium chloride-   NH₄OAc ammonium acetate-   Pd(OAc)₂ palladium(II) acetate-   Pd(PPh₃)₄ tetrakis(triphenylphosphine)palladium(0)-   PG protecting group-   Ph phenyl-   Pr propyl-   i-Pr isopropyl-   i-PrOH or IPA isopropanol-   Rt retention time-   SiO₂ silica oxide-   SFC supercritical fluid chromatography-   TEA triethylamine-   TFA trifluoroacetic acid-   TFAA Trifluoroacetic anhydride-   THF tetrahydrofuran-   TiCl₄ titanium tetrachloride-   T₃P 1-propanephosphonic acid cyclic anhydride

The compounds of the present invention can be synthesized using themethods described below, together with synthetic methods known in theart of synthetic organic chemistry, or by variations thereon asappreciated by those skilled in the art. Preferred methods include, butare not limited to, those described below. The reactions are performedin a solvent or solvent mixture appropriate to the reagents andmaterials employed and suitable for the transformations being effected.It will be understood by those skilled in the art of organic synthesisthat the functionality present on the molecule should be consistent withthe transformations proposed. This will sometimes require a judgment tomodify the order of the synthetic steps or to select one particularprocess scheme over another in order to obtain a desired compound of theinvention.

The novel compounds of this invention may be prepared using thereactions and techniques described in this section. Also, in thedescription of the synthetic methods described below, it is to beunderstood that all proposed reaction conditions, including choice ofsolvent, reaction atmosphere, reaction temperature, duration of theexperiment and workup procedures, are chosen to be the conditionsstandard for that reaction, which should be readily recognized by oneskilled in the art. Restrictions to the substituents that are compatiblewith the reaction conditions will be readily apparent to one skilled inthe art and alternate methods must then be used.

Synthesis

The compounds of Formula (I) may be prepared by the exemplary processesdescribed in the following schemes and working examples, as well asrelevant published literature procedures that are used by one skilled inthe art. Exemplary reagents and procedures for these reactions appearhereinafter and in the working examples. Protection and de-protection inthe processes below may be carried out by procedures generally known inthe art (see, for example, Wuts, P. G. M. et al., Protecting Groups inOrganic Synthesis, 4th Edition, Wiley (2007)). General methods oforganic synthesis and functional group transformations are found in:Trost, B. M. et al., eds., Comprehensive Organic Synthesis: Selectivity,Strategy & Efficiency in Modern Organic Chemistry, Pergamon Press, NewYork, N.Y. (1991); Smith, M. B. et al., March's Advanced OrganicChemistry: Reactions, Mechanisms, and Structure. 6th Edition, Wiley &Sons, New York, N.Y. (2007); Katritzky, A. R. et al, eds., ComprehensiveOrganic Functional Groups Transformations II, 2nd Edition, ElsevierScience Inc., Tarrytown, N.Y. (2004); Larock, R. C., ComprehensiveOrganic Transformations, VCH Publishers, Inc., New York, N.Y. (1999),and references therein.

As a person of ordinary skill in the art would be able to understandthat a pyridone in a molecule may tautomerize to its keto and enol formsas shown in the following equation, wherein R¹, R², R³, and R⁴ are asdefined above, this disclosure is intended to cover all possibletautomers even when a structure depicts only one of them.

Description of Analytical LCMS Methods:

Method A: Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7 μmparticles; Mobile Phase A: 5:95 ACN:water with 10 mM NH₄OAc; MobilePhase B: 95:5 ACN:water with 10 mM NH₄OAc; Temperature: 50° C.;Gradient: 0-100% B over 3 minutes, then a 0.75 minute hold at 100% B;Flow: 1.11 mL/min; Detection: UV at 220 nm.

Method B: Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7 μmparticles; Mobile Phase A: 5:95 ACN:water with 0.1% TFA; Mobile Phase B:95:5 ACN:water with 0.1% TFA; Temperature: 50° C.; Gradient: 0-100% Bover 3 minutes, then a 0.75 minute hold at 100% B; Flow: 1.11 mL/min;Detection: UV at 220 nm.

Method C: Column: PHENOMENEX® Luna 3 m C18 (2.0×30 mm); Mobile Phase A:10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90:10 MeOH:water with0.1% TFA; Gradient: 0-100% B over 2 minutes, then a 1 minute hold at100% B; Flow: 1 mL/min; Detection: UV at 220 nm.

Method D: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7 μm particles;Mobile Phase A: water with 0.1% TFA; Mobile Phase B: ACN with 0.1% TFA;Gradient: 2-98% B over 1 minute, then a 0.5 minute hold at 98% B; Flow:0.8 mL/min; Detection: UV at 220 nm.

Generic Schemes

Step 1 describes the preparation of compounds of Formula G1c from acompound of Formula G1a, by acylating with a nitriles of Formula G1b inthe presence of a Lewis acid (like AlMe₃ or TMSOTF). Preferred solventsare aprotic solvents (such as toluene and the like).

Step 2 describes the preparation of pyrimidine compounds of Formula G1dfrom compounds of formula G1c by condensation with triethylmethanetricarboxylate with or without base. Preferred solvents areaprotic solvents (like toluene and xylenes). Preferred bases aretertiary amines (such as TEA, DIEA and the like) and alkaline metalalkoxides (such as sodium ethoxide and the like). The condensation mayalso be accomplished with TMSCl in preferred solvents such as1,2-dichloroethane.

Step 3 describes the preparation of compounds of Formula (I) byconversion of the ester of compounds of Formula G1d to an amide (NR₃R₄).The conversion of compounds of Formula G1d to compounds of Formula (I)can be accomplished from the amine (NR₃R₄) in the presence of a Lewisacid (for example, AlMe₃ or Zr(OtBu)₄) with or without the addition of acoupling agent (for example, HOAt) in solvents such as toluene.

IV. Biology

APJ receptor was discovered in 1993 as an orphan G protein-coupledreceptor (GPCR) and was subsequently found to recognize apelin peptideas its endogenous ligand. It belongs to class A of GPCRs and has aclassical 7-transmembrane domain structure, exhibiting greatest sequencehomology to angiotensin AT1 receptor (for review see Pitkin, S. L. etal., Pharmacol. Rev., 62(3):331-342 (2010)). APJ is expressed in widevariety of peripheral tissues and the CNS, and has relatively highexpression in placenta, myocardium, vascular endothelial cells, smoothmuscle cells as well as cardiac myocytes (Kleinz, J. M. et al.,Pharmacol. Ther., 107(2):198-211(2005)). Apelin peptide was originallyidentified in bovine stomach extract and remains to date the only knownendogenous ligand and agonist of APJ receptor (Tatemoto, K. et al.,Biochem. Biophys. Res. Commun., 255:471-476 (1998)). Tissue expressionof apelin gene mirrors closely the APJ expression pattern and has beenpostulated to act in an autocrine or paracrine manner, often exemplifiedby reference to “apelin-APJ system”. Apelin gene encodes 77 amino acidprecursor peptide that is cleaved to form mature secreted peptideundergoing further proteolytic cleavage forming shorter C-terminalfragments. Apelin-36, -17 and -13 represent the maj or active forms withthe pyroglutamated form of apelin-13 being the most stable and the mostabundant form present in the cardiac tissue (Maguire, J. J. et al.,Hypertension, 54(3):598-604 (2009)). Apelin has very short half life incirculation, estimated to be less than 5 minutes (Japp, A. G. et al.,Circulation, 121(16):1818-1827 (2010)).

Activation of APJ receptor is known to inhibit forskolin-stimulatedcyclic AMP (cAMP) levels in pertussis toxin-sensitive manner, indicatingcoupling to the Gi proteins. The binding affinity of apelin and the EC₅₀values in the cAMP assay are reported to be in the sub-nanomolar range(for review see Pitkin, S. L. et al., Pharmacol. Rev.,62(3):331-342(2010)). In addition to cAMP inhibition, APJ receptoractivation also leads to β-arrestin recruitment, receptorinternalization and activation of extracellular-regulated kinases (ERKs)(for review see Kleinz, J. M. et al., Pharmacol. Ther.,107(2):198-211(2005)). Which of these signaling mechanisms contribute to modulation ofdownstream physiological effects of apelin is not clear at present. APJreceptor has been shown to interact with the AT1 receptor. While apelindoes not bind AT1 and angiotensin II does not bind APJ, it has beenpostulated that certain physiological actions of apelin are mediated, atleast in part, via functional antagonism of the angiotensin II and AT1receptor pathway (Chun, A. J. et al., J. Clin. Invest.,118(10):3343-3354 (2008)).

It is also desirable and preferable to find compounds with advantageousand improved characteristics compared with known HF treatment agents, inone or more of the following categories that are given as examples, andare not intended to be limiting: (a) pharmacokinetic properties,including oral bioavailability, half life, and clearance; (b)pharmaceutical properties; (c) dosage requirements; (d) factors thatdecrease blood drug concentration peak-to-trough characteristics; (e)factors that increase the concentration of active drug at the receptor;(f) factors that decrease the liability for clinical drug-druginteractions; (g) factors that decrease the potential for adverseside-effects, including selectivity versus other biological targets; and(h) improved therapeutic index.

As used herein, the term “patient” encompasses all mammalian species.

As used herein, the term “subject” refers to any human or non-humanorganism that could potentially benefit from treatment with an APJagonist. Exemplary subjects include human beings of any age with riskfactors for development of heart failure and the sequelae thereof,angina, ischemia, cardiac ischemia, myocardial infarction, reperfusioninjury, angioplastic restenosis, hypertension, vascular complications ofdiabetes, obesity or endotoxemia, stroke, as well as atherosclerosis,coronary artery disease, acute coronary syndrome, and/or dyslipidemias.

As used herein, “treating” or “treatment” cover the treatment of adisease-state in a mammal, particularly in a human, and include: (a)inhibiting the disease-state, i.e., arresting it development; and/or (b)relieving the disease-state, i.e., causing regression of the diseasestate.

As used herein, “prophylaxis” or “prevention” cover the preventivetreatment of a subclinical disease-state in a mammal, particularly in ahuman, aimed at reducing the probability of the occurrence of a clinicaldisease-state. Patients are selected for preventative therapy based onfactors that are known to increase risk of suffering a clinical diseasestate compared to the general population. “Prophylaxis” therapies can bedivided into (a) primary prevention and (b) secondary prevention.Primary prevention is defined as treatment in a subject that has not yetpresented with a clinical disease state, whereas secondary prevention isdefined as preventing a second occurrence of the same or similarclinical disease state.

As used herein, “risk reduction” covers therapies that lower theincidence of development of a clinical disease state. As such, primaryand secondary prevention therapies are examples of risk reduction.

“Therapeutically effective amount” is intended to include an amount of acompound of the present invention that is effective when administeredalone or in combination to modulate APJ and/or to prevent or treat thedisorders listed herein. When applied to a combination, the term refersto combined amounts of the active ingredients that result in thepreventive or therapeutic effect, whether administered in combination,serially, or simultaneously.

A. Assay Methods

Intracellular cAMP Accumulation Assay

HEK293 cells stably expressing human APJ receptor were used to assessthe activity of compounds. Cultured cells were detached and resuspendedin the cAMP Homogeneous Time-Resolved Fluorescence (HTRF) assay buffer(Cisbio cat; #62AM4PEJ). The assay was performed in 384-well assayplates (Perkin-Elmer; cat #6008289) according to assay protocol providedby the manufacturer. Serial dilutions of a compound together with assaybuffer containing 0.2 nM IBMX and 2 μM forskolin were added to each wellcontaining 5,000 cells and incubated for 30 minutes at room temperature.Subsequently, cAMP D2 reagent was added in the lysis buffer followed bythe EuK antibody (Cisbio; cat #62AM4PEJ) and incubated for 60 min. Thefluorescence emission ratio was measured using fluorometer. Theintracellular cAMP concentrations (compound-stimulated inhibition offorskolin-mediated cAMP production) were calculated by extrapolationfrom a standard curve using known cAMP concentrations. The EC₅₀ valueswere obtained by fitting the data to a sigmoidal concentration-responsecurve with variable slope. The maximal achievable inhibition offorskolin-induced cAMP levels (Y_(max)) for each compound was expressedas relative percentage of inhibition attained using pyroglutamatedapelin-13 ((Pyr1)apelin-13) peptide, which was set to 100%.

The examples disclosed below were tested in the APJ in vitro assaysdescribed above and were found having human APJ cyclic AMP (hcAMP)activity. The EC₅₀ value of each compound is presented at the end of theexample description.

The compounds of the present invention possess activity as agonists ofAPJ receptor, and, therefore, may be used in the treatment of diseasesassociated with APJ activity. Accordingly, the compounds of the presentinvention can be administered to mammals, preferably humans, for thetreatment of a variety of conditions and disorders, including, but notlimited to, treating, preventing, or slowing the progression of heartfailure, coronary artery disease, peripheral vascular disease,atherosclerosis, diabetes, metabolic syndrome and the sequelae ofthereof, hypertension, pulmonary hypertension, cerebrovasculardisorders, atrial fibrillation, angina, ischemia, stroke, myocardialinfarction, acute coronary syndrome, reperfusion injury, angioplasticrestenosis, vascular complications of diabetes and obesity.

The biological activity of the exemplified compounds of this inventiondetermined by the assay described above is shown at the end of eachexample. The APJ cAMP EC₅₀ potency ranges are as follows: A=0.01-10 nM;B=10.01-100 nM; C=100.01-300 nM.

V. Pharmaceutical Compositions, Formulations and Combinations

The compounds of this invention can be administered for any of the usesdescribed herein by any suitable means, for example, orally, such astablets, capsules (each of which includes sustained release or timedrelease formulations), pills, powders, granules, elixirs, tinctures,suspensions (including nanosuspensions, microsuspensions, spray-drieddispersions), syrups, and emulsions; sublingually; bucally;parenterally, such as by subcutaneous, intravenous, intramuscular, orintrastemal injection, or infusion techniques (e.g., as sterileinjectable aqueous or non-aqueous solutions or suspensions); nasally,including administration to the nasal membranes, such as by inhalationspray; topically, such as in the form of a cream or ointment; orrectally such as in the form of suppositories. They can be administeredalone, but generally will be administered with a pharmaceutical carrierselected on the basis of the chosen route of administration and standardpharmaceutical practice.

The term “pharmaceutical composition” means a composition comprising acompound of the invention in combination with at least one additionalpharmaceutically acceptable carrier. A “pharmaceutically acceptablecarrier” refers to media generally accepted in the art for the deliveryof biologically active agents to animals, in particular, mammals,including, i.e., adjuvant, excipient or vehicle, such as diluents,preserving agents, fillers, flow regulating agents, disintegratingagents, wetting agents, emulsifying agents, suspending agents,sweetening agents, flavoring agents, perfuming agents, antibacterialagents, antifungal agents, lubricating agents and dispensing agents,depending on the nature of the mode of administration and dosage forms.

Pharmaceutically acceptable carriers are formulated according to anumber of factors well within the purview of those of ordinary skill inthe art. These include, without limitation: the type and nature of theactive agent being formulated; the subject to which the agent-containingcomposition is to be administered; the intended route of administrationof the composition; and the therapeutic indication being targeted.Pharmaceutically acceptable carriers include both aqueous andnon-aqueous liquid media, as well as a variety of solid and semi-soliddosage forms. Such carriers can include a number of differentingredients and additives in addition to the active agent, suchadditional ingredients being included in the formulation for a varietyof reasons, e.g., stabilization of the active agent, binders, etc., wellknown to those of ordinary skill in the art. Descriptions of suitablepharmaceutically acceptable carriers, and factors involved in theirselection, are found in a variety of readily available sources such as,for example, Allen, Jr., L. V. et al., Remington: The Science andPractice of Pharmacy (2 Volumes), 22nd Edition, Pharmaceutical Press(2012),

The dosage regimen for the compounds of the present invention will, ofcourse, vary depending upon known factors, such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the species, age, sex, health, medical condition, andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; the route ofadministration, the renal and hepatic function of the patient, and theeffect desired.

By way of general guidance, the daily oral dosage of each activeingredient, when used for the indicated effects, will range betweenabout 0.001 to about 5000 mg per day, preferably between about 0.01 toabout 1000 mg per day, and most preferably between about 0.1 to about250 mg per day. Intravenously, the most preferred doses will range fromabout 0.01 to about 10 mg/kg/minute during a constant rate infusion.Compounds of this invention may be administered in a single daily dose,or the total daily dosage may be administered in divided doses of two,three, or four times daily.

The compounds are typically administered in admixture with suitablepharmaceutical diluents, excipients, or carriers (collectively referredto herein as pharmaceutical carriers) suitably selected with respect tothe intended form of administration, e.g., oral tablets, capsules,elixirs, and syrups, and consistent with conventional pharmaceuticalpractices.

Dosage forms (pharmaceutical compositions) suitable for administrationmay contain from about 1 milligram to about 2000 milligrams of activeingredient per dosage unit. In these pharmaceutical compositions theactive ingredient will ordinarily be present in an amount of about0.1-95% by weight based on the total weight of the composition.

A typical capsule for oral administration contains at least one of thecompounds of the present invention (250 mg), lactose (75 mg), andmagnesium stearate (15 mg). The mixture is passed through a 60 meshsieve and packed into a No. 1 gelatin capsule.

A typical injectable preparation is produced by aseptically placing atleast one of the compounds of the present invention (250 mg) into avial, aseptically freeze-drying and sealing. For use, the contents ofthe vial are mixed with 2 mL of physiological saline, to produce aninjectable preparation.

The present invention includes within its scope pharmaceuticalcompositions comprising, as an active ingredient, a therapeuticallyeffective amount of at least one of the compounds of the presentinvention, alone or in combination with a pharmaceutical carrier.Optionally, compounds of the present invention can be used alone, incombination with other compounds of the invention, or in combinationwith one or more other therapeutic agent(s), e.g., agents used intreatment of heart failure or other pharmaceutically active material.

The compounds of the present invention may be employed in combinationwith other APJ agonists or one or more other suitable therapeutic agentsuseful in the treatment of the aforementioned disorders including:agents for treating heart failure, anti-hypertensive agents,anti-atherosclerotic agents, anti-dyslipidemic agents, anti-diabeticagents, anti-hyperglycemic agents, anti-hyperinsulinemic agents,anti-thrombotic agents, anti-retinopathic agents, anti-neuropathicagents, anti-nephropathic agents, anti-ischemic agents, anti-obesityagents, anti-hyperlipidemic agents, anti-hypertriglyceridemic agents,anti-hypercholesterolemic agents, anti-restenotic agents,anti-pancreatic agents, lipid lowering agents, anorectic agents, memoryenhancing agents, anti-dementia agents, cognition promoting agents,appetite suppressants, and agents for treating peripheral arterialdisease.

The compounds of the present invention may be employed in combinationwith additional therapeutic agent(s) selected from one or more,preferably one to three, of the following therapeutic agents in treatingheart failure and coronary artery disease: ACE inhibitors, β-blockers,diuretics, mineralocorticoid receptor antagonists, renin inhibitors,calcium channel blockers, angiotensin II receptor antagonists, nitrates,digitalis compounds, inotropic agents and β-receptor agonists,anti-hyperlipidemic agents, plasma HDL-raising agents,anti-hypercholesterolemic agents, cholesterol biosynthesis inhibitors(such as HMG CoA reductase inhibitors), LXR agonist, probucol,raloxifene, nicotinic acid, niacinamide, cholesterol absorptioninhibitors, bile acid sequestrants (such as anion exchange resins, orquaternary amines (e.g., cholestyramine or colestipol), low densitylipoprotein receptor inducers, clofibrate, fenofibrate, benzofibrate,cipofibrate, gemfibrizol, vitamin B₆, vitamin B₁₂, anti-oxidantvitamins, anti-diabetes agents, platelet aggregation inhibitors,fibrinogen receptor antagonists, aspirin and fibric acid derivatives.

The compounds of the invention may be used in combination with one ormore, preferably one to three, of the following anti-diabetic agentsdepending on the desired target therapy. Studies indicate that diabetesand hyperlipidemia modulation can be further improved by the addition ofa second agent to the therapeutic regimen. Examples of anti-diabeticagents include, but are not limited to, sulfonylureas (such aschlorpropamide, tolbutamide, acetohexamide, tolazamide, glyburide,gliclazide, glynase, glimepiride, and glipizide), biguanides (such asmetformin), thiazolidinediones (such as ciglitazone, pioglitazone,troglitazone, and rosiglitazone), and related insulin sensitizers, suchas selective and non-selective activators of PPARα, PPARβ and PPARγ;dehydroepiandrosterone (also referred to as DHEA or its conjugatedsulphate ester, DHEA-SO₄); anti-glucocorticoids; TNFα inhibitors;dipeptidyl peptidase IV (DPP4) inhibitor (such as sitagliptin,saxagliptin), GLP-1 agonists or analogs (such as exenatide),α-glucosidase inhibitors (such as acarbose, miglitol, and voglibose),pramlintide (a synthetic analog of the human hormone amylin), otherinsulin secretagogues (such as repaglinide, gliquidone, andnateglinide), insulin, as well as the therapeutic agents discussed abovefor treating heart failure and atherosclerosis.

The compounds of the invention may be used in combination with one ormore, preferably one to three, of the following anti-obesity agentsselected from phenylpropanolamine, phentermine, diethylpropion,mazindol, fenfluramine, dexfenfluramine, phentiramine, β₃-adrenergicreceptor agonist agents; sibutramine, gastrointestinal lipase inhibitors(such as orlistat), and leptins. Other agents used in treating obesityor obesity-related disorders include neuropeptide Y, enterostatin,cholecytokinin, bombesin, amylin, histamine H₃ receptors, dopamine D₂receptor modulators, melanocyte stimulating hormone, corticotrophinreleasing factor, galanin and gamma amino butyric acid (GABA).

The above other therapeutic agents, when employed in combination withthe compounds of the present invention may be used, for example, inthose amounts indicated in the Physicians' Desk Reference, as in thepatents set out above, or as otherwise determined by one of ordinaryskill in the art.

Particularly when provided as a single dosage unit, the potential existsfor a chemical interaction between the combined active ingredients. Forthis reason, when the compound of the present invention and a secondtherapeutic agent are combined in a single dosage unit they areformulated such that although the active ingredients are combined in asingle dosage unit, the physical contact between the active ingredientsis minimized (that is, reduced). For example, one active ingredient maybe enteric coated. By enteric coating one of the active ingredients, itis possible not only to minimize the contact between the combined activeingredients but also to control the release of one of these componentsin the gastrointestinal tract such that one of these components is notreleased in the stomach but rather is released in the intestines. One ofthe active ingredients may also be coated with a material that affects asustained-release throughout the gastrointestinal tract and also servesto minimize physical contact between the combined active ingredients.Furthermore, the sustained-released component can be additionallyenteric coated such that the release of this component occurs only inthe intestine. Still another approach would involve the formulation of acombination product in which the one component is coated with asustained and/or enteric release polymer, and the other component isalso coated with a polymer such as a low viscosity grade ofhydroxypropyl methylcellulose (HPMC) or other appropriate materials asknown in the art, in order to further separate the active components.The polymer coating serves to form an additional barrier to interactionwith the other component.

These as well as other ways of minimizing contact between the componentsof combination products of the present invention, whether administeredin a single dosage form or administered in separate forms but at thesame time by the same manner, will be readily apparent to those skilledin the art, once armed with the present disclosure.

The compounds of the present invention can be administered alone or incombination with one or more additional therapeutic agents. By“administered in combination” or “combination therapy” it is meant thatthe compound of the present invention and one or more additionaltherapeutic agents are administered concurrently to the mammal beingtreated. When administered in combination, each component may beadministered at the same time or sequentially in any order at differentpoints in time. Thus, each component may be administered separately butsufficiently closely in time so as to provide the desired therapeuticeffect.

The compounds of the present invention are also useful as standard orreference compounds, for example as a quality standard or control, intests or assays involving the APJ receptor and apelin activity. Suchcompounds may be provided in a commercial kit, for example, for use inpharmaceutical research involving APJ and apelin or anti-heart failureactivity. For example, a compound of the present invention could be usedas a reference in an assay to compare its known activity to a compoundwith an unknown activity. This would ensure the experimenter that theassay was being performed properly and provide a basis for comparison,especially if the test compound was a derivative of the referencecompound. When developing new assays or protocols, compounds accordingto the present invention could be used to test their effectiveness.

The compounds of the present invention may also be used in diagnosticassays involving APJ and apelin.

The present invention also encompasses an article of manufacture. Asused herein, article of manufacture is intended to include, but not belimited to, kits and packages. The article of manufacture of the presentinvention, comprises: (a) a first container; (b) a pharmaceuticalcomposition located within the first container, wherein the composition,comprises a first therapeutic agent, comprising a compound of thepresent invention or a pharmaceutically acceptable salt form thereof;and, (c) a package insert stating that the pharmaceutical compositioncan be used for the treatment and/or prophylaxis of multiple diseases ordisorders associated with APJ and apelin (as defined previously). Inanother embodiment, the package insert states that the pharmaceuticalcomposition can be used in combination (as defined previously) with asecond therapeutic agent for the treatment and/or prophylaxis ofmultiple diseases or disorders associated with APJ and apelin. Thearticle of manufacture can further comprise: (d) a second container,wherein components (a) and (b) are located within the second containerand component (c) is located within or outside of the second container.Located within the first and second containers means that the respectivecontainer holds the item within its boundaries.

The first container is a receptacle used to hold a pharmaceuticalcomposition. This container can be for manufacturing, storing, shipping,and/or individual/bulk selling. First container is intended to cover abottle, jar, vial, flask, syringe, tube (e.g., for a cream preparation),or any other container used to manufacture, hold, store, or distribute apharmaceutical product.

The second container is one used to hold the first container and,optionally, the package insert. Examples of the second containerinclude, but are not limited to, boxes (e.g., cardboard or plastic),crates, cartons, bags (e.g., paper or plastic bags), pouches, and sacks.The package insert can be physically attached to the outside of thefirst container via tape, glue, staple, or another method of attachment,or it can rest inside the second container without any physical means ofattachment to the first container. Alternatively, the package insert islocated on the outside of the second container. When located on theoutside of the second container, it is preferable that the packageinsert is physically attached via tape, glue, staple, or another methodof attachment. Alternatively, it can be adjacent to or touching theoutside of the second container without being physically attached.

The package insert is a label, tag, marker, etc. that recitesinformation relating to the pharmaceutical composition located withinthe first container. The information recited will usually be determinedby the regulatory agency governing the area in which the article ofmanufacture is to be sold (e.g., the United States Food and DrugAdministration). Preferably, the package insert specifically recites theindications for which the pharmaceutical composition has been approved.The package insert may be made of any material on which a person canread information contained therein or thereon. Preferably, the packageinsert is a printable material (e.g., paper, plastic, cardboard, foil,adhesive-backed paper or plastic, etc.) on which the desired informationhas been formed (e.g., printed or applied).

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments that are given forillustration of the invention and are not intended to be limitingthereof.

VI. Examples

The following Examples are offered as illustrative, as a partial scopeand particular embodiments of the invention and are not meant to belimiting of the scope of the invention. Abbreviations and chemicalsymbols have their usual and customary meanings unless otherwiseindicated. Unless otherwise indicated, the compounds described hereinhave been prepared, isolated and characterized using the schemes andother methods disclosed herein or may be prepared using the same.

Example 12-Butyl-5-(3-(5-chloropyridin-2-yl)pyrrolidine-1-carbonyl)-1-(2,6-dimethoxyphenyl)-6-hydroxypyrimidin-4(1H)-one

Compound 1a. Ethyl 2-(2,6-dimethoxyphenyl)acetate

To a solution of pentanenitrile (310 mg, 3.7 mmol) and2-methoxy-6-methylaniline (518 mg, 3.40 mmol) in toluene (13 mL) at RTwas added a solution of trimethylaluminum in toluene (1.7 mL, 3.4 mmol)at 0° C. The reaction mixture was heated at 110° C. for 1 h. The cooledreaction mixture was quenched with saturated solution of Rochelle's salt(5 mL) and stirred at RT for 30 min. The reaction mixture was extractedwith EtOAc (3×20 mL). The combined organic layer was washed with brine,dried over MgSO₄, filtered and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography eluting with 20-100%EtOAc/hexanes with 0.5% Et₃N to give Compound 1a (450 mg, 56%) as abrown oil. LCMS (Method D) retention time=0.65 min, m/z=237.1 (M+H). ¹HNMR (500 MHz, chloroform-d) δ 6.88 (t, J=8.4 Hz, 1H), 6.51 (d, J=8.3 Hz,2H), 4.68-3.89 (m, 2H), 3.71 (s, 6H), 2.33 (br. s., 2H), 1.84-1.52 (m,2H), 1.49-1.24 (m, 2H), 0.89 (br. s., 3H).

Compound 1b. Ethyl 2-butyl-1-(2,6-dimethoxyphenyl)-6-hydroxy-4-oxo-1,4-dihydropyrimidine-5-carboxylate

A mixture of 1a (500 mg, 2.1 mmol) and triethyl methanetricarboxylate(590 mg, 2.5 mmol) in toluene (12 mL) was heated at 140° C. for 1 h in amicrowave reactor. The reaction mixture was concentrated under reducedpressure and the residue was purified by silica gel chromatographyeluting with 0-100% EtOAc/DCM to give Compound 1b (170 mg, 22%) as abrown solid. LCMS (Method D) retention time=0.87 min, m/z=377.3 (M+H).¹H NMR (400 MHz, chloroform-d) δ 7.39 (t, J=8.5 Hz, 1H), 6.65 (d, J=8.6Hz, 2H), 4.40 (q, J=7.2 Hz, 2H), 3.78 (s, 6H), 2.49-2.18 (m, 2H),1.70-1.53 (m, 2H), 1.39 (t, J=7.2 Hz, 3H), 1.29-1.12 (m, 2H), 0.79 (t,J=7.3 Hz, 3H).

Compound 1c. 5-Chloro-2-(pyrrolidin-3-yl)pyridine

Compound 1d. tert-Butyl3-(5-chloropyridin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate

A mixture of tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate(commercially available, 106 mg, 0.360 mmol), 2-bromo-5-chloropyridine(76 mg, 0.40 mmol), cesium carbonate (350 mg, 1.10 mmol) andPdCl₂(dppf)-CH₂C₁₂ (18 mg, 0.022 mmol) in dioxane (2.4 mL) and water(0.5 mL) was degassed and heated at 90° C. for 14 h. The mixture wasdiluted with EtOAc, washed with brine, dried over sodium sulfate,filtered and concentrated under reduced pressure. The residue wassubjected to silica gel chromatography eluting with 0-100% EtOAc/hexaneto give 1d (50 mg, 0.18 mmol, 50% yield) as a yellow solid. ¹H NMR (400MHz, chloroform-d) δ 8.62-8.41 (m, 1H), 7.82-7.57 (m, 1H), 7.40-7.16 (m,1H), 6.60-6.32 (m, 1H), 4.60-4.49 (m, 2H), 4.41-4.27 (m, 2H), 1.52-1.45(m, 9H).

Compounds 1e and 1f. tert-Butyl3-(5-chloropyridin-2-yl)pyrrolidine-1-carboxylate

A mixture of 1d (530 mg, 1.90 mmol) and 5% Rh/C (390 mg, 0.190 mmol) inEtOH (8 mL) was stirred under hydrogen atmosphere (balloon) for 4 h. Themixture was filtered through Celite and concentrated under reducedpressure. The residue was purified using silica gel chromatographyeluting with 0-100% EtOAc/hexane, followed by chiral SFC preparativeHPLC (column: Chiralpak IC, 30×250 mm, 5 micron; mobile phase: 10%IPA/0.1% DEA/90% CO₂; flow condition: 85 mL/min, 150 bar, 40° C.;wavelength: 220 nm) to give Compound 1e (designated as Isomer 1, 110 mg,21% yield). Peak 1 retention time=11.87 and Compound 1f (designated asIsomer 2, 118 mg, 22% yield). Peak 2 retention time=13.24 (Chiralpak IC,4.6×250 mm, 5 micron; mobile phase: 10% IPA/0.1% DEA/90% CO₂; flowcondition: 2.0 mL/min, 150 bar, 40° C.; wavelength: 220 nm. LCMS (MethodB) Rt=0.96 min, m/z=283.2 (M+H). ¹H NMR (400 MHz, chloroform-d) δ 8.52(d, J=2.2 Hz, 1H), 7.64-7.56 (m, 1H), 7.14 (d, J=8.4 Hz, 1H), 3.97-3.29(m, 5H), 2.34-2.05 (m, 2H), 1.50-1.44 (m, 9H).

Compound 1c. tert-Butyl3-(5-chloropyridin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (HCl salt)

Compound 1e (110 mg, 0.38 mmol) and 4N HCl/dioxane (1.0 mL, 4.0 mmol)was stirred at rt for 5 h. The mixture was diluted with diethyl ether,and the solid was collected by filtration to give Compound 1c (89 mg,0.35 mmol, 91% yield) as a white solid. LCMS (Method B) Rt=0.47 min,m/z=183.1 (M+H). ¹H NMR (500 MHz, DMSO-d₆) δ 7.79 (d, J=2.5 Hz, 1H),7.24-6.97 (m, 1H), 6.83-6.56 (m, 1H), 3.01 (s, 1H), 2.83 (s, 2H),2.77-2.67 (m, 1H), 2.54 (br. s., 2H), 1.85-1.57 (m, 1H), 1.53-1.14 (m,1H).

Example 1.2-Butyl-5-(3-(5-chloropyridin-2-yl)pyrrolidine-1-carbonyl)-1-(2,6-dimethoxyphenyl)-6-hydroxypyrimidin-4(1H)-one

A mixture of Compound 1b (15 mg, 0.040 mmol), Compound 1c (10 mg, 0.040mmol) and DIEA (0.021 mL, 0.12 mmol) were dissolved in EtOH (0.5 mL) washeated at 160° C. for 1.5 h. Example 1 was isolated by prep HPLC (5.3mg, 10 μmol, 26% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 8.55 (br. s., 1H),7.92-7.77 (m, 1H), 7.52-7.27 (m, 2H), 6.83 (br. s., 2H), 3.99-3.45 (m,5H), 2.51 (br. s., 6H), 2.22 (br. s., 4H), 1.42 (br. s., 2H), 1.22-1.10(m, 2H), 0.70 (d, J=6.3 Hz, 3H). LCMS retention time=0.78 min,(M+H)+=513.3. (BEH C18, 1.5×50 mm, flow rate 2 mL/min, 1 min gradientwith 2-98% ACN/water/0.2% TFA). Human APJ cAMP EC₅₀ potency range A.

Example 2(R)-2-Butyl-1-(2,6-dicyclopropylphenyl)-6-hydroxy-5-(3-phenylpyrrolidine-1-carbonyl)pyrimidin-4(1H)-one

Example 2a. 2,6-Dicyclopropylaniline

A mixture of 2,6-dibromoaniline (0.50 g, 2.0 mmol), cyclopropylboronicacid (0.70 g, 8.0 mmol), potassium phosphate (1.7 g, 8.0 mmol) andtricyclohexylphosphine (0.11 g, 0.40 mmol) in toluene (5 mL) and water(2 ml) was degassed with nitrogen then palladium acetate (0.12 g, 0.52mmol) was added. The mixture was heated at 100° C. for 14 h. Thereaction mixture was allowed to cool and ethyl acetate was added and theresulting mixture was washed with water, brine, dried over sodiumsulfate and concentrated under reduced pressure. The residue waspurified on silica gel chromatography eluting with 0-50% EtOAc/hexane togive Compound 2a (240 mg, 68%) as a yellow oil. LCMS (Method D)retention time=0.80 min, m/z=174.2 (M+H). ¹H NMR (400 MHz, DMSO-d₆) δ6.84 (d, J=7.7 Hz, 2H), 6.71-6.62 (m, 1H), 1.82 (tt, J=8.3, 5.4 Hz, 2H),0.99-0.91 (m, 4H), 0.64-0.53 (m, 4H).

Example 2.(R)-2-Butyl-1-(2,6-dicyclopropylphenyl)-6-hydroxy-5-(3-phenylpyrrolidine-1-carbonyl)pyrimidin-4(1H)-one

Example 2 was prepared from Compound 2a following a similar procedure asdescribed for Compound 1 (39% yield) as a clear oil. LCMS (Method A)retention time=1.05 min, m/z=498.2 (M+H). ¹H NMR (400 MHz, chloroform-d)δ 7.37-7.11 (m, 6H), 6.80 (d, J=7.3 Hz, 2H), 3.95-3.22 (m, 4H),2.39-2.24 (m, 3H), 2.08-1.92 (m, 1H), 1.72 (br. s., 3H), 1.43 (br. s.,2H), 1.31-1.17 (m, 3H), 0.91-0.57 (m, 11H). Human APJ cAMP Potency rangeA.

Example 31-(2,6-Dimethoxyphenyl)-2-(ethoxymethyl)-6-hydroxy-5-(3-(pyridin-2-yl)pyrrolidine-1-carbonyl)pyrimidin-4(1H)-one

Compound 3a. 2-Ethoxyacetamide

To a stirred solution of 2-ethoxyacetic acid (1.5 g, 14 mmol) in DCM (20mL) at 0° C. was added oxalyl chloride (8.65 mL, 17.3 mmol), followed byDMF (2 drops). Cooling was removed and the reaction mixture was stirredat RT for 3 h. The reaction mixture was concentrated under reducedpressure and dissolved in DCM (20 mL). Ammonia (20.6 mL, 144 mmol) (7 Min MeOH) was added carefully and the reaction mixture stirred for 16 h.The reaction mixture was concentrated under reduced pressure, dissolvedin DCM, filtered and washed with DCM. The filtrate was concentratedunder reduced pressure to give Compound 3a (1.0 g, 67%) as a whitesolid. ¹H NMR (500 MHz, CDCl₃) δ 6.51 (br s, 1H), 5.46 (br s, 1H), 3.94(s, 2H), 3.59 (q, J=6.8 Hz, 2H), 1.25 (t, J=7.2 Hz, 3H).

Compound 3b. 2-Ethoxyacetonitrile

To a stirred solution of Compound 3a (1.0 g, 9.7 mmol) in THF (10 mL) at0° C. was added pyridine (1.57 mL, 19.4 mmol) followed by TFAA (6.85 mL,48.5 mmol). The reaction mixture was stirred at RT for 1 h. AqueousNaHCO₃ solution was added carefully to the reaction mixture until pH=8was attained. The reaction mixture was extracted with CH₂C₁₂ (2×). Thecombined organic layers were washed with 1N HCl, dried over MgSO₄,filtered and concentrated in vacuo to give Compound 3b (0.80 g, 97%) asa yellow liquid. ¹H NMR (500 MHz, CDCl₃) δ 4.24 (s, 2H), 3.66 (q, J=6.9Hz, 2H), 1.27 (t, J=6.9 Hz, 3H).

Compound 3c. N-(2,6-Dimethoxyphenyl)-2-ethoxyacetimidamide

Trimethylaluminum (2 M in toluene, 4.70 ml, 9.40 mmol) was addeddropwise to a solution of 2,6-dimethoxyaniline (1.2 g, 7.8 mmol) andCompound 3b (0.80 g, 9.4 mmol) in toluene (10 ml) while cooling in anice bath. After addition was complete, the reaction mixture was heatedto 110° C. and was stirred at this temperature for 14 h. The reactionmixture was allowed to cool and was partitioned between a saturatedsolution of Rochelle's salt and EtOAc. The organic phase was separated,dried over MgSO₄, filtered and concentrated under reduced pressure. Theresidue was added to a silica gel (120 g) column and was eluted with0-20% of 20% MeOH/DCM in 0.5% TEA/DCM to give Compound 3c (1.1 g, 57%)as a brown liquid. MS m/z=239.0 (M+H). ¹H NMR (500 MHz, CDCl₃) δ 7.01(t, J=8.3 Hz, 1H), 6.62 (d, J=7.7 Hz, 2H), 5.32 (s, 2H), 4.88 (br s,2H), 4.31 (s, 2H), 3.82 (s, 6H), 3.62-3.73 (m, 2H), 1.19-1.33 (m, 3H).

Example 3

Example 3 was prepared from Compound 3c following a similar procedure asdescribed for example 1 (1.2 mg, 1%) as a colorless film. LCMS (MethodA) retention time=1.15 min, m/z=505.9 (M+H). ¹H NMR (500 MHz, DMSO-d₆) δ7.87 (d, J=7.9 Hz, 1H), 7.78 (d, J=8.5 Hz, 1H), 7.69 (t, J=7.6 Hz, 1H),7.43 (t, J=7.9 Hz, 1H), 7.42 (t, J=7.0 Hz, 1H), 6.81 (d, J=8.5 Hz, 2H),4.80 (s, 2H), 3.95 (s, 2H), 3.76 (s, 6H), 3.33 (q, J=6.7 Hz, 2H), 1.01(t, J=6.7 Hz, 3H). Human APJ cAMP Potency range A.

Example 4(S)-2-(2-Cyclopropylethyl)-1-(2,6-dimethoxyphenyl)-6-hydroxy-5-(3-phenylpyrrolidine-1-carbonyl)pyrimidin-4(1H)-one

Compound 4a. 2-Cyclopropylethyl 4-methylbenzenesulfonate

To 2-cyclopropylethanol at 0° C. (0.98 g, 11 mmol) and pyridine (2.4 mL,30 mmol) in DCM (15 mL) was added 4-methylbenzene-1-sulfonyl chloride(22 g, 11 mmol). The cold bath was removed and the mixture allowed towarm to room temperature for 14 h. The reaction mixture was diluted withwater and Et₂O and the phases were separated. The organic phase waswashed sequentially with water, 10% aqueous HCl and brine, dried (MgSO₄)filtered and concentrated under reduced pressure to give Compound 4a(2.0 g, 74%) as a clear colorless oil. Compound 4a was used in the nextstep without further purification. MS m/z=241.4 (M+H). ¹H NMR (400 MHz,chloroform-d) δ 7.77 (d, J=8.1 Hz, 2H), 7.32 (d, J=8.4 Hz, 2H), 4.06 (t,J=6.7 Hz, 2H), 2.42 (s, 3H), 1.56-1.45 (m, 2H), 0.70-0.57 (m, 1H),0.44-0.32 (m, 2H), 0.04-0.10 (m, 2H).

Compound 4b. 3-Cyclopropylpropanenitrile

To a solution of Compound 4a (1.0 g, 4.2 mmol) in DMF (5 mL) was addedNaCN (0.60 g, 13 mmol) and TBAI (0.06 g, 0.2 mmol) and the reactionmixture was stirred at 90° C. for 14 h. The reaction mixture was allowedto cool to room temperature, diluted with Et₂O and brine and the phaseswere separated. The organic phase was washed with 10% aqueous LiCl,dried over MgSO₄, filtered and concentrated under reduced pressure togive Compound 4b (0.39 g, 99%) as a clear colorless oil, which was usedin the next step without further purification. ¹H NMR (chloroform-d) δ2.27 (t, J=7.2 Hz, 2H), 1.34-1.46 (m, 2H), 0.62-0.74 (m, 1H), 0.34-0.45(m, 2H), −0.05-0.04 (m, 2H).

Compound 4c. 3-Cyclopropyl-N-(2,6-dimethoxyphenyl)propanimidamide

To a mixture of Compound 4b (0.37 g, 3.9 mmol) and 2,6-dimethoxyaniline(0.5 g, 3 mmol) in toluene (5 mL), at 0° C., was added a 2M solution oftrimethylaluminum in hexane (2 ml, 4 mmol) dropwise. The reactionmixture was allowed to warm to room temperature and heated at 110° C.overnight. The reaction mixture was allowed to cool to RT and quenchedwith saturated aqueous Rochelle's salt and EtOAc. The phases wereseparated, the aqueous phase was extracted with EtOAc. The organicphases were combined and washed with brine, dried over MgSO₄, filteredand concentrated under reduced pressure. The residue was purified bysilica gel chromatography eluting with 0 to 30% MeOH/0.5% TEA in DCM togive Compound 4c (0.35 g, 44% yield) as an orange oil. MS m/z=249.4(M+H). ¹H NMR (methanol-d₄) δ 7.01 (t, J=8.3 Hz, 1H), 6.64 (d, J=8.3 Hz,2H), 2.29-2.48 (m, 2H), 1.50-1.67 (m, 2H), 0.78-0.93 (m, 1H), 0.44 (s,2H), 0.02-0.16 (m, 2H).

Example 4

Example 4 was prepared from Compound 4c following a similar procedure asdescribed for example 1 (15 mg, 59%) as a colorless film. LCMS (MethodA) retention time=1.42 min, m/z=490.3 (M+H). ¹H NMR (500 MHz, DMSO-d₆) δ7.22-7.29 (m, 1H), 7.06-7.21 (m, 4H), 6.70-6.83 (m, 2H), 3.18-3.88 (m,14H), 2.27-2.36 (m, 3H), 2.12-2.23 (m, 1H), 1.83-1.99 (m, 1H), 0.85 (dd,J=5.85, 15.44 Hz, 6H). Human APJ cAMP Potency range A.

Example 5(R)-1-(2,6-Bis(methoxy-d₃)phenyl)-2-butyl-6-hydroxy-5-(3-phenylpyrrolidine-1-carbonyl)pyrimidin-4(1H)-one

Compound 5a. 1,3-Di[²H₃]methoxy-2-nitrobenzene

To a solution of 2-nitrobenzene-1,3-diol (1.75, 11.0 mmol) in acetone(175 mL) was added methyl-d₃ iodide (4.9 g, 34 mmol) and K₂CO₃ (3.1 g,23 mmol). The reaction mixture was stirred at 65° C. for 14 h. Aftercooling to RT, the mixture was concentrated under reduced pressure. Theresidue was diluted with water and extracted with EtOAc (3×). Thecombined extracts were washed with brine, dried over MgSO₄, filtered andconcentrated under reduced pressure. The residue was purified by silicagel chromatography eluting with 0 to 80% EtOAc/hexanes to give Compound5a (1.4 g, 66%) as a light yellow foam. MS m/z=190.4 (M+H). ¹H NMR(chloroform-d) δ 7.25 (t, J=8.5 Hz, 1H), 6.55 (d, J=8.4 Hz, 2H).

Compound 5b. 2,6-Di[²H₃]methoxyaniline

To a solution of Compound 5a (1.4 g, 7.5 mmol) in a mixture of AcOH (40mL), EtOH (40 mL) and H₂O (20 mL) was added iron (2.5 g, 45 mmol)portionwise and the reaction mixture was stirred at 90° C. for 14 h. Thereaction mixture was allowed to cool to RT, poured onto ice, basifiedcarefully with the addition of solid Na₂CO₃ and extracted with EtOAc(3×). The combined organic extracts were washed with brine, dried overMgSO₄, filtered and concentrated under reduced pressure to give Compound5b (1.2 g, 97%) as a dark solid. Compound 5a was used without furtherpurification. MS m/z=160.4 (M+H).

Compound 5c. N-(2,6-Di[²H₃]methoxyphenyl)pentanimidamide

To a mixture of Compound 4b (1.2 g, 7.2 mmol) and pentanenitrile (0.72g, 8.6 mmol) in toluene (11 mL) at 0° C. was added 2M trimethylaluminumin hexane (4.3 mL, 8.6 mmol) dropwise. The reaction mixture was allowedto warm to room temperature and was heated at 100° C. for 14 h. Thereaction mixture was allowed to cool to RT and quenched with saturatedaqueous Rochelle's salt and EtOAc. The phases were separated and theaqueous phase was extracted with EtOAc. The organic phases were combinedand washed with brine, dried (MgSO₄), filtered and concentrated underreduced pressure. The residue was purified by silica gel chromatographyeluting with 0 to 30% MeOH/0.5% TEA in DCM to give Compound 5c (1.1 g,64%) as an orange oil. MS m/z=243.4 (M+H). ¹H NMR (methanol-d₄) δ 7.01(t, J=8.3 Hz, 1H), 6.64 (d, J=8.4 Hz, 2H), 2.22-2.34 (m, 2H), 1.60-1.72(m, 2H), 1.40-1.53 (m, 2H), 0.96 (t, J=6.7 Hz, 3H).

Compound 5d. Ethyl2-butyl-1-(2,6-di[²H₃]methoxyphenyl)-6-hydroxy-4-oxo-1,4-dihydropyrimidine-5-carboxylate

A solution of Compound 5c (0.35 g, 1.4 mmol) and triethylmethanetricarboxylate (0.50 g, 2.2 mmol) in toluene (10 ml) was heatedat 155° C. in a microwave reactor for 15 min. The reaction mixture wasconcentrated under reduced pressure. The residue was purified by silicagel chromatography eluting with 0 to 100% EtOAc/hexanes to give Compound5d (0.18 g, 33%) as a pale yellow solid. MS m/z=383.4 (M+H). ¹H NMR(methanol-d₄) δ 7.88 (t, J=8.5 Hz, 1H), 7.22 (d, J=8.3 Hz, 2H), 4.73 (q,J=7.1 Hz, 2H), 2.75 (t, J=7.7 Hz, 2H), 1.88-1.97 (m, 2H), 1.72 (t, J=7.2Hz, 3H), 1.56-1.65 (m, 2H), 1.16 (t, J=7.4 Hz, 3H)

Example 5.(R)-1-(2,6-Bis(methoxy-d₃)phenyl)-2-butyl-6-hydroxy-5-(3-phenylpyrrolidine-1-carbonyl)pyrimidin-4(1H)-one

Compound 5 was prepared by the general procedures described in Example 1(21 mg, 83%). LCMS (Method A) Rt=1.44 min, m/z=484.0 (M+H). ¹H NMR (500MHz, DMSO-d₆) δ 7.22-7.29 (m, 1H), 7.06-7.21 (m, 4H), 6.70-6.83 (m, 2H),3.18-3.88 (m, 14H), 2.27-2.36 (m, 3H), 2.12-2.23 (m, 1H), 1.83-1.99 (m,1H), 0.85 (dd, J=5.85, 15.44 Hz, 6H) Human APJ cAMP Potency range A.

Example 6.2-butyl-6-hydroxy-3-((S)-1-phenylpropyl)-5-((R)-3-phenylpyrrolidine-1-carbonyl)pyrimidin-4(3H)-one

Compound 6a. Ethyl Pentanimidate Hydrochloride

Pentanenitrile (9 mL, 90 mmol) in EtOH (59.9 mL, 1030 mmol) was cooledto 0° C. by ice bath. AcCl (48.64 mL, 685.0 mmol) was added dropwiseover 3 hours. After complete addition, the reaction mixture was stirredat room temperature for 14 h. The resulting solution was concentratedunder reduced pressure and the residue washed with Et₂O (2×) to removeresidual HCl. The solid was suspended in 200 ml of Et₂O and stored at 4°C. for 14 h. Compound 6a (14 g, 85 mmol, 99% yield) was obtained byfiltration as a white solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ 4.64 (d,J=6.6 Hz, 2H), 2.74 (t, J=7.5 Hz, 2H), 1.87-1.64 (m, 2H), 1.49 (t, J=6.2Hz, 3H), 1.45-1.38 (m, 2H), 0.95 (t, J=7.3 Hz, 3H).

Compound 6b. (S)—N-(1-phenylpropyl)pentanimidamide

To a solution of Compound 6a (1.35 g, 8.15 mmol) in Ethanol (15 mL) wasadded (S)-1-phenylpropan-1-amine (0.918 g, 6.79 mmol) at 0° C. Thereaction mixture was stirred from 0° C. to room temperature for 14 h,followed by addition of ammonia in MeOH (14.55 mL, 102.0 mmol) and wasstirred at room temperature for 2 hours. The reaction mixture wasconcentrated and the residual was dissolved in MeOH and purified by prepHPLC. The fractions containing Compound 6b were collected andconcentrated under reduced pressure. The residue was dissolved in DCMand washed with 1N NaOH. The combined organic layer was washed withbrine and concentrated to Compound 6b (710 mg, 3.25 mmol, 47.9% yield)as colorless oil. MS m/z=219 [M+H]⁺. ¹H NMR (400 MHz, CHLOROFORM-d) δ7.29-7.05 (m, 5H), 4.41 (br. s., 1H), 2.23-2.05 (m, 2H), 1.91-1.62 (m,2H), 1.55-1.38 (m, 2H), 1.27 (sxt, J=7.4 Hz, 2H), 0.83 (td, J=7.4, 2.0Hz, 6H).

Compound 6c. (S)-ethyl2-butyl-4-hydroxy-6-oxo-1-(1-phenylpropyl)-1,6-dihydropyrimidine-5-carboxylate

A mixture of Compound 6b (710 mg, 3.25 mmol), triethylmethanetricarboxylate (1.241 mL, 5.85 mmol) and Toluene (15 mL) washeated at 160° C. for 1 hour in microwave reactor. The mixture wascooled to room temperature and loaded onto a 40 g ISCO column elutedwith 0-70% EtOAc/DCM for 30 min. The desired fraction was collected andconcentrated to give Compound 6c (580 mg, 1.27 mmol, 39.0% yield). MSm/z=359.3 [M+H]⁺. ¹H NMR (400 MHz, METHANOL-d₄ at 333K) δ 7.43-7.35 (m,2H), 7.33-7.26 (m, 3H), 6.26 (br. s., 1H), 4.43-4.30 (m, 2H), 2.75-2.51(m, 3H), 2.47-2.24 (m, 1H), 1.67-1.51 (m, 1H), 1.40-1.28 (m, 4H),1.26-1.13 (m, 2H), 1.04 (t, J=7.4 Hz, 3H), 0.79 (t, J=7.4 Hz, 3H). ¹³CNMR (101 MHz, METHANOL-d₄ at 333K) δ 171.0, 169.5, 162.5, 140.7, 130.1,128.7, 127.7, 93.0, 62.9, 60.3, 36.1, 30.4, 30.3, 25.7, 23.3, 14.6,13.9, 11.5.

Compound 6.2-Butyl-6-hydroxy-3-((S)-1-phenylpropyl)-5-((R)-3-phenylpyrrolidine-1-carbonyl)pyrimidin-4(3H)-one

To a solution of Compound 6c (50 mg, 0.139 mmol) and(R)-3-phenylpyrrolidine, HCl (33.3 mg, 0.181 mmol) in Ethanol (1 mL) wasadded DIEA (0.073 mL, 0.418 mmol). The mixture was stirred in microwavereactor at 160° C. for 1 hour. The crude sample was diluted with MeOHand purified with prep HPLC (4 injections): Phenomenex AXIA Luna 75×30mm 5 u: A: 10% ACN −90% H₂O −10 mM TFA B: 90% ACN −10% H₂O −10 mM TFAwavelength 254 nm; flow rate 40 mL/min; gradient time 10 min; 0 to 100%B. Compound 6 (31 mg, 0.067 mmol, 48.4% yield) was obtained. LCMS(Method A) Rt=1.75 min, MS m/z=460.1 [M+H]⁺. ¹H NMR (400 MHz,CHLOROFORM-d at 333K) δ 7.40-7.08 (m, 10H), 6.11 (br. s., 1H), 3.88-3.09(m, 5H), 2.81-2.22 (m, 5H), 2.00 (quin, J=10.1 Hz, 1H), 1.69 (br. s.,1H), 1.58-1.38 (m, 1H), 1.27 (d, J=6.4 Hz, 2H), 1.04 (t, J=7.4 Hz, 3H),0.84 (t, J=6.7 Hz, 3H).

Example 71-(2,6-dimethoxyphenyl)-6-hydroxy-5-(3-(2-methoxyphenyl)pyrrolidine-1-carbonyl)-2-(5-methylpyridin-3-yl)pyrimidin-4(1H)-one

Compound 7a. N-(2,6-dimethoxyphenyl)-5-methylnicotinimidamide

To a solution of 2,6-dimethoxyaniline (0.51 g, 3.3 mmol) and5-methylnicotinonitrile (0.39 g, 3.3 mmol) in toluene (10 ml) at 0° C.was added dropwise TMS-OTf (1.2 ml, 6.5 mmol). The resulting mixture wasstirred at 0° C. for 10 min and heated to 110° C. for 2 days. Thereaction mixture was cooled to 0° C., quenched with 1N HCl (10 mL)solution and diluted with EtOAc. The organic layer was washed with 1NHCl solution and dried over sodium sulfate, decanted and concentrated togive a brown oil. The residue was added to a silica gel (40 g) columnand was eluted with 0-100% 1% Et₃N/EtOAc in DCM. Collected fractions togive Compound 7a (0.65 g, 73% yield) as an off white solid. MS m/z=272.2(M+H). 1H NMR (500 MHz, CHLOROFORM-d) δ 8.90 (s, 1H), 8.56 (s, 1H), 8.24(s, 1H), 7.07 (t, J=8.3 Hz, 1H), 6.68 (d, J=8.3 Hz, 2H), 4.76 (br s,2H), 3.84 (s, 6H), 2.43 (s, 3H).

Compound 7b. ethyl1-(2,6-dimethoxyphenyl)-6-hydroxy-2-(5-methylpyridin-3-yl)-4-oxo-1,4-dihydropyrimidine-5-carboxylate

To a mixture of Compound 7a (75 mg, 0.28 mmol) and triethylmethanetricarboxylate (96 mg, 0.42 mmol) in Et₃N (1.5 mL, 11 mmol) wasadded TMSCl (0.53 mL, 4.2 mmol) at 0° C. The mixture was stirred for 10min and heated to 110° C. for 20 hrs. The reaction mixture wasconcentrated in vacuo and diluted with EtOAc. The organic layer waswashed with 0.1M HCl. The organic layer was dried over MgSO₄, filteredand concentrated in vacuo. The residue was added to a silica gel (12 g)column and was eluted with 0-100% EtOAc in hexanes, then 0-100% 1%TEA/EtOAc in DCM. Collected fractions to give Compound 7b (100 mg, 88%yield) as a yellow solid. MS m/z=412.2 (M+H). 1H NMR (500 MHz,CHLOROFORM-d) δ 8.37 (s, 1H), 8.34 (s, 1H), 7.57 (s, 1H), 7.24 (t, J=8.5Hz, 1H), 6.47 (d, J=8.5 Hz, 2H), 4.76 (br s, 2H), 3.84 (s, 6H), 2.43 (s,3H).

Example 7.1-(2,6-dimethoxyphenyl)-6-hydroxy-5-(3-(2-methoxyphenyl)pyrrolidine-1-carbonyl)-2-(5-methylpyridin-3-yl)pyrimidin-4(1H)-one

To a stirred mixture of Compound 7b (12 mg, 0.029 mmol) and Compound 7c,isomer 1 (6.7 mg, 0.038 mmol) in toluene (1 ml) was addedtrimethylaluminum (0.029 ml, 0.058 mmol) dropwise. The reaction mixturewas heated at 110° C. for 3 hrs. The reaction mixture was concentratedin vacuo and diluted with EtOAc/THF. The organic layer was washed withsat NH₄Cl. The organic layer was dried over MgSO₄, filtered andconcentrated in vacuo. The residue was purified via preparative LC/MSwith the following conditions: Column: XBridge C18, 19×200 mm, 5-mparticles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile: water with 10 mM ammoniumacetate; Gradient: 5-45% B over 19 minutes, then a 5-minute hold at 100%B; Flow: 20 mL/min. Fractions containing the desired product werecombined and dried via centrifugal evaporation to give Example 7 (3.7mg, 24%). LCMS (Method A) Rt=1.37 min, m/z=543.1 (M+H). 1H NMR (500 MHz,DMSO-d₆) □ 8.27-8.29 (m, 1H), 8.13-8.16 (m, 1H), 7.41-7.43 (m, 1H), 7.28(t, J=7.2 Hz, 1H), 7.19-7.26 (m, 2H), 6.96-7.01 (m, 1H), 6.89-6.92 (m,1H), 6.53-6.61 (m, 2H), 3.76-3.85 (m, 6H), 3.65-3.70 (m, 3H), 3.37-3.63(m, 5H), 2.17 (s, 3H), 2.11-2.15 (m, 1H), 1.92-2.02 (m, 1H). Human APJcAMP Potency range A.

Example 8(R)-2-(but-3-en-1-yl)-6-hydroxy-3-(2-methoxy-6-methylphenyl)-5-(3-phenylpyrrolidine-1-carbonyl)pyrimidin-4(3H)-one,diastereomer 1 and diastereomer 2

Compound 8a. N-(2-methoxy-6-methylphenyl)pent-4-enimidamidetrimethylaluminum (6.6 ml, 13 mmol) was added dropwise to a solution of2-methoxy-6-methylaniline (1.5 g, 11 mmol) and pent-4-enenitrile (1.1 g,13 mmol) in Toluene (10 ml) while cooling in an ice bath. After additionwas complete, the reaction mixture was heated to 110° C. for 16 hrs. Thereaction mixture was allowed to cool to RT and partitioned betweensaturated solution of Rochelle's salt and EtOAc. The organic phase wasdried, filtered and concentrated. The residue was added to a silica gel(120 g) column and was eluted with 0-20% 0.5% Et₃N/DCM in 20% MeOH/DCM.Collected fractions to give Compound 8a (2.4 g, 100% yield) as an offwhite solid. MS m/z=219.1 (M+H). 1H NMR (500 MHz, CHLOROFORM-d) δ 6.93(t, J=7.7 Hz, 1H), 6.83 (d, J=7.4 Hz, 1H), 6.78 (d, J=8.0 Hz, 1H),5.94-6.06 (m, 1H), 5.16 (d, J=17.1 Hz, 1H), 5.07 (d, J=9.9 Hz, 1H), 4.27(br s, 2H), 3.79 (s, 3H), 2.53-2.59 (m, 2H), 2.45-2.53 (m, 2H), 2.14 (s,3H).

Compound 8b. ethyl2-(but-3-en-1-yl)-6-hydroxy-1-(2-methoxy-6-methylphenyl)-4-oxo-1,4-dihydropyrimidine-5-carboxylate

A mixture of Compound 8a (15 mg, 0.069 mmol), acetic acid (7.9 μl, 0.14mmol) and triethyl methanetricarboxylate (32 mg, 0.14 mmol) in toluene(1 ml) was heated at 140° C. for 105 min in a microwave reactor. Thereaction mixture was concentrated in vacuo. The residue was added to asilica gel (12 g) column and was eluted with 20-100% EtOAc in hexanes.Collected fractions to give Compound 8b (24 mg, 100% yield) as a clearliquid. MS m/z=359.1 (M+H). 1H NMR (500 MHz, CHLOROFORM-d) δ 7.33 (t,J=8.3 Hz, 1H), 6.94 (d, J=7.4 Hz, 1H), 6.86 (d, J=8.3 Hz, 1H), 5.67-5.75(m, 1H), 4.93-4.98 (m, 2H), 4.42 (q, J=7.2 Hz, 2H), 3.77 (s, 3H),2.29-2.48 (m, 4H), 2.09 (s, 3H), 1.39 (t, J=7.2 Hz, 3H).

Example 8 and Example 8″ were prepared from compound 8b following asimilar procedure as described for compound 1. The residue was purifiedvia preparative LC/MS with the following conditions: Column: XBridgeC18, 19×200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile: waterwith 10-μM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: waterwith 10-μM ammonium acetate; Gradient: 15-55% B over 20 minutes, then a5-minute hold at 100% B; Flow: 20 mL/min. The first eluting fraction wascollect and the stereochemistry was assigned as Example 8 (11 mg, 33%).LCMS (Method A) Rt=1.36 min, m/z=460.4 (M+H). 1H NMR (500 MHz, DMSO-d₆)δ 7.21-7.41 (m, 6H), 6.95-7.08 (m, 2H), 5.67-5.76 (m, 1H), 4.87-4.98 (m,2H), 3.64-3.81 (m, 5H), 3.27-3.47 (3H), 2.18-2.34 (m, 5H), 1.90-2.06 (m,4H). Human APJ cAMP Potency range A.

The second eluting fraction was collect and the stereochemistry wasassigned as Example 8″ (3.4 mg, 11%). LCMS (Method A) Rt=1.37 min,m/z=460.4 (M+H). 1H NMR (500 MHz, DMSO-d₆) δ 7.20-7.41 (m, 6H),6.95-7.07 (m, 2H), 5.65-5.77 (m, 1H), 4.88-4.97 (m, 2H), 3.63-3.79 (m,5H), 3.28-3.52 (3H), 2.19-2.34 (m, 5H), 1.89-2.06 (m, 4H). Human APJcAMP Potency range A.

Example 9.1-(2,6-dimethoxyphenyl)-6-hydroxy-2-(isopropoxymethyl)-5-(3-(p-tolyl)azetidine-1-carbonyl)pyrimidin-4(1H)-one

Compound 9a. tert-butyl 3-iodoazetidine-1-carboxylate

To a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (400 mg,2.31 mmol) in toluene (23 ml), imidizole (472 mg, 6.93 mmol),triphenylphosphine (1.21 g, 4.62 mmol) and iodine (879 mg, 3.46 mmol)were added successively and the reaction mixture was heated at 110° C.for 4 h. The cooled reaction mixture was quenched with saturated aqueousNaHCO₃ and extracted with Et₂O (2×). The Et₂O layers were combined andthe composite was treated with iodine until a persistent brown coloroccurred and the mixture was stirred at RT overnight. The Et₂O solutionwas treated with saturated aqueous Na₂S₂O₃ until colorless, the phaseswere split and the organic phase was dried over MgSO₄, filtered andconcentrated under reduced pressure. The residue was purified by silicagel chromatography eluting with 0 to 20% EtOAc in hexane to giveCompound 9a (594 mg, 91% yield) as a clear colorless oil. MS m/z=284.0,(M+H) 1H NMR (CHLOROFORM-d) δ: 4.57 (t, J=8.4 Hz, 2H), 4.36-4.44 (m,1H), 4.18-4.26 (m, 2H), 1.37 (s, 9H).

Compound 9b. tert-butyl 3-(p-tolyl)azetidine-1-carboxylate

To a 0° C. solution of compound a (100 mg, 0.35 mmol),(1R,2R)—N1,N1,N2,N2-tetramethylcyclohexane-1,2, diamine (3.61 mg, 0.0210mmol) and 0.05M cobalt(II) chloride in THF (0.35 ml, 0.018 mmol) wasadded 0.5M p-tolylmagnesium bromide (0.848 ml, 0.424 mmol) dropwise. Thereaction mixture was allowed to cool to RT and was stirred for 14 h. Thereaction mixture was quenched with saturated aqueous NH₄C₁ and extractedwith Et₂O (2×). The Et₂O layers were combined and the composite wasdried over MgSO₄, filtered and concentrated under reduced pressure. Theresidue was purified by silica gel chromatography eluting with 0 to 20%EtOAc in hexane to give Compound 9b (72 mg, 82% yield) as a clearcolorless oil. MS m/z=249.2 (M+H), 1H NMR (CHLOROFORM-d) δ: 7.01-7.22(m, 4H), 4.16-4.32 (m, 2H), 3.81-3.95 (m, 2H), 3.54-3.71 (m, 1H), 2.25(s, 3H), 1.38 (s, 9H).

Compound 9c. 3-(p-tolyl)azetidine

To a solution of compound b (71.5 mg, 0.289 mmol) in DCM (2 ml) wasadded TFA (165 mg, 1.45 mmol) and the reaction mixture was stirred at RTfor 1 h. The reaction mixture was concentrated under reduced pressure togive compound 9c that was used without further purification (76 mg, 100%yield) as a yellow oil. MS m/z=148.1 (M+H), (M+H) 1H NMR (CHLOROFORM-d)δ: 7.06-7.22 (m, 4H), 4.23-4.33 (m, 2H), 4.07-4.22 (m, 3H), 2.21-2.33(s, 3H)

Lengthy table referenced here US20170275272A1-20170928-T00001 Pleaserefer to the end of the specification for access instructions.

LENGTHY TABLES The patent application contains a lengthy table section.A copy of the table is available in electronic form from the USPTO website(http://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20170275272A1).An electronic copy of the table will also be available from the USPTOupon request and payment of the fee set forth in 37 CFR 1.19(b)(3).

What is claimed is:
 1. A compound of Formula (I):

or a stereoisomer, an enantiomer, a diastereoisomer, a tautomer, or apharmaceutically acceptable salt thereof, wherein: alk is C₁₋₆ alkylenesubstituted with 0-5 R^(e); ring B is independently selected from C₃₋₆cycloalkyl, C₃₋₆ cycloalkenyl, aryl, bicyclic carbocyclyl, and6-membered heteroaryl; R¹, at each occurrence, is independently selectedfrom H, halogen, NO₂, —(CH₂)_(n)OR^(b), (CH₂)_(n)S(O)_(p)R_(c),—(CH₂)_(n)C(═O)R^(b), —(CH₂)_(n)NR^(a)R^(a), —(CH₂)_(n)CN,—(CH₂)_(n)C(═O)NR^(a)R^(a), —(CH₂)_(n)NR^(a)C(═O)R^(b),—(CH₂)_(n)NR^(a)C(═O)NR^(a)R^(a), —(CH₂)_(n)NR^(a)C(═O)OR^(b),—(CH₂)_(n)OC(═O)NR^(a)R^(a), —(CH₂)_(n)C(═O)OR^(b),(CH₂)_(n)S(O)_(p)NR^(a)R^(a), —(CH₂)_(n)NR^(a)S(O)_(p)NR^(a)R^(a),—(CH₂)_(n)NR^(a)S(O)_(p)R_(c), C₁₋₄ alkyl substituted with 0-3 R^(e),—(CH₂)_(n)—C₃₋₆ carbocyclyl substituted with 0-3 R^(e), and—(CH₂)_(n)-heterocyclyl substituted with 0-3 R^(e); R² is independentlyselected from C₁₋₁₀ alkyl substituted with 0-3 R^(e); C₂₋₅ alkenylsubstituted with 0-3 R^(e), aryl substituted with 0-3 R^(e), heteroarylsubstituted with 0-3 R^(e), and C₃₋₆ cycloalkyl substituted with 0-3R^(e); provided when R² is C₁₋₁₀ alkyl, the carbon atoms and the groupsattached thereto except the carbon atom attached to the pyrimidine ringmay be replaced by O, N, and S; R³ is independently selected from H andC₁₋₅ alkyl: R⁴ is independently selected from —(CR⁷R⁷)_(n)—R⁶,—(CR⁷R⁷)_(n)OR⁶, —(CR⁷R⁷)_(n)S(O)_(p)R⁶, —(CR⁷R⁷)_(n)C(═O)R⁶,—(CR⁷R⁷)_(n)NR^(a)R⁶, —(CR⁷R⁷)_(n)NR^(a)C(═O)R⁶,—(CR⁷R⁷)_(n)S(O)_(p)NR^(a)R⁶, and —(CR⁷R⁷)_(n)NR^(a)S(O)_(p)R⁶;alternatively, R³ and R⁴ together with the nitrogen atom to which theyare both attached form a heterocyclic ring or a spiro heterocyclic ringcomprising carbon atoms and additional 1 to 4 heteroatoms selected fromNR^(a), O, and S and substituted with 0-5 R⁵; R⁵, at each occurrence, isindependently selected from OH, halogen, —(CR⁷R⁷)_(n)—R⁶, —OR⁶,—S(O)_(p)R⁶, —C(═O)R⁶, —NR^(a)R⁶, —C(═O)NR^(a)R⁶, —NR^(a)C(═O)R⁶,—NR^(a)C(═O)OR⁶, —OC(═O)NR^(a)R⁶, —C(═O)OR⁶, —S(O)_(p)NR^(a)R⁶,—NR^(a)S(O)_(p)NR^(a)R⁶, and —NR^(a)S(O)_(p)R⁶; R^(5a), at eachoccurrence, is independently selected from —C(═O)OR⁶, C(═O)NR^(a)R⁶,—(CR⁷R⁷)_(n)—R⁶, —C(═O)—R⁶, and —S(O)_(p)R⁶; R⁶, at each occurrence, isindependently selected from —(CR⁷R⁷)_(n)—C₃₋₁₀ carbocyclyl and—(CR⁷R⁷)_(n)-heteroaryl, each substituted with 0-3 R⁸; R⁷, at eachoccurrence, is independently selected from H, C₁₋₄ alkyl, and—(CH₂)_(n)—C₃₋₁₂ carbocyclyl substituted with 0-3 R^(e); R⁸, at eachoccurrence, is independently selected from H, halogen, —(CH₂)_(n)OR^(b),═O, (CH₂)_(n)S(O)_(p)R_(c), —(CH₂)_(n)C(═O)R^(b), —(CH₂)_(n)NR^(a)R^(a),—(CH₂)_(n)CN, —(CH₂)_(n)C(═O)NR^(a)R^(a), —(CH₂)_(n)NR^(a)C(═O)R^(b),—(CH₂)_(n)NR^(a)C(═O)NR^(a)R^(a), —(CH₂)_(n)NR^(a)C(═O)OR^(b),—(CH₂)_(n)OC(═O)NR^(a)R^(a), —(CH₂)_(n)C(═O)OR^(b),(CH₂)_(n)S(O)_(p)NR^(a)R^(a), —(CH₂)_(n)NR^(a)S(O)_(p)NR^(a)R^(a),—(CH₂)_(n)NR^(a)S(O)_(p)R_(c), C₁₋₅ alkyl substituted with 0-3 R^(e),—(CH₂)_(n)—C₃₋₆ carbocyclyl substituted with 0-3 R^(e), and—(CH₂)_(n)-heterocyclyl substituted with 0-3 R^(e); R^(a), at eachoccurrence, is independently selected from H, C₁₋₆ alkyl substitutedwith 0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5 R^(e), C₂₋₆ alkynylsubstituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e); orR^(a) and R^(a) together with the nitrogen atom to which they are bothattached form a heterocyclic ring substituted with 0-5 R^(e); R^(b), ateach occurrence, is independently selected from H, C₁₋₆ alkylsubstituted with 0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5 R^(e),C₂₋₆ alkynyl substituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclylsubstituted with 0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted with0-5 R^(e); R^(c), at each occurrence, is independently selected fromC₁₋₆ alkyl substituted with 0-5 R^(e), C₂₋₆alkenyl substituted with 0-5R^(e), C₂₋₆alkynyl substituted with 0-5 R^(e), C₃₋₆carbocyclyl, andheterocyclyl; R^(e), at each occurrence, is independently selected fromF, Cl, Br, CN, NO₂, ═O, CO₂H, C₁₋₆ alkyl substituted with 0-5 R_(f),C₂₋₆ alkenyl, C₂₋₆ alkynyl, —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)—C₄₋₆heterocyclyl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, —(CH₂)_(n)OR_(f),—S(O)_(p)R_(f), —C(═O)NR^(f)R_(f), —NR^(f)C(═O)R^(f),—S(O)_(p)NR^(f)R_(f), —NR^(f)S(O)_(p)R^(f), —NR^(f)C(═O)OR_(f),—OC(═O)NR^(f)R_(f) and —(CH₂)_(n)NR^(f)R_(f); R^(f), at each occurrence,is independently selected from H, F, Cl, Br, CN, OH, C₁₋₅alkyl(optionally substituted with halogen and OH), C₃₋₆ cycloalkyl, andphenyl, or R^(f) and R^(f) together with the nitrogen atom to which theyare both attached form a heterocyclic ring optionally substituted withC₁₋₄alkyl; n, at each occurrence, is independently selected from zero,1, 2, 3, and 4; and p, at each occurrence, is independently selectedfrom zero, 1, and
 2. 2. The compound according to claim 1, or astereoisomer, an enantiomer, a diastereoisomer, a tautomer, or apharmaceutically acceptable salt thereof, wherein: R¹, at eachoccurrence, is independently selected from H, F, Cl, Br, NO₂,—(CH₂)_(n)OR^(b), —(CH₂)_(n)C(═O)R^(b), —(CH₂)_(n)NR^(a)R^(a),—(CH₂)_(n)CN, —(CH₂)_(n)C(═O)NR^(a)R^(a), —(CH₂)_(n)NR^(a)C(═O)R^(b),C₁₋₄ alkyl substituted with 0-3 R^(e), and C₃₋₆ cycloalkyl substitutedwith 0-3 R^(e); R² is independently selected from C₁₋₅ alkyl substitutedwith 0-3 R^(e); C₂₋₅ alkenyl, aryl substituted with 0-3 R^(e),heteroaryl substituted with 0-3 R^(e), C₃₋₆ cycloalkyl,—(CH₂)₁₋₄OC₁₋₅alkyl, —(CH₂)₁₋₄NHC₁₋₅alkyl, and —(CH₂)₁₋₃OC₃₋₆cycloalkyl;R³ and R⁴ together with the nitrogen atom to which they are bothattached form a heterocyclic ring or a spiro heterocyclic ring selectedfrom

R⁵, at each occurrence, is independently selected from OH,—(CR⁷R⁷)_(n)—R⁶, —OR⁶, —S(O)_(p)R⁶, —C(═O)R⁶, —NR^(a)R⁶, —C(═O)NR^(a)R⁶,—NR^(a)C(═O)R⁶, —NR^(a)C(═O)OR⁶, —OC(═O)NR^(a)R⁶, —C(═O)OR⁶,—S(O)_(p)NR^(a)R⁶, —NR^(a)S(O)_(p)NR^(a)R⁶, and —NR^(a)S(O)_(p)R⁶;R^(5a), at each occurrence, is independently selected from —C(═O)OR⁶,—C(═O)NR^(a)R⁶, —(CR⁷R⁷)_(n)—R⁶, —C(═O)—R⁶, and —S(O)_(p)R⁶; R⁶, at eachoccurrence, is independently selected from —(CR⁷R⁷)_(n)-aryl,—(CR⁷R⁷)_(n)—C₃₋₆ cycloalkyl, and —(CR⁷R⁷)_(n)-heteroaryl, eachsubstituted with 0-3 R⁸; R⁷, at each occurrence, is independentlyselected from H, C₁₋₄ alkyl, and —(CH₂)_(n)—C₃₋₁₂ carbocyclylsubstituted with 0-3 R^(e); R⁸, at each occurrence, is independentlyselected from H, F, Cl, Br, —OR^(b), —(CH₂)_(n)C(═O)R^(b),—(CH₂)_(n)C(═O)OR^(b), —(CH₂)_(n)NR^(a)R^(a), CN,—(CH₂)_(n)C(═O)NR^(a)R^(a), —NHC(═O)OR^(b), C₁₋₄ alkyl substituted with0-3 R^(e), (CH₂)_(n)—C₃₋₆ carbocyclyl substituted with 0-3 R^(e), and—(CH₂)_(n)-heterocyclyl substituted with 0-3 R^(e); R^(a), at eachoccurrence, is independently selected from H, C₁₋₆ alkyl substitutedwith 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e),and —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e); or R^(a) andR^(a) together with the nitrogen atom to which they are both attachedform a heterocyclic ring substituted with 0-5 R^(e); R^(b), at eachoccurrence, is independently selected from H, C₁₋₆ alkyl substitutedwith 0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5 R^(e), C₂₋₆ alkynylsubstituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e);R^(e), at each occurrence, is independently selected from F, Cl, Br, CN,NO₂, ═O, —CO₂H, C₁₋₆ alkyl substituted with 0-5 R_(f), C₂₋₆ alkenyl,C₂₋₆ alkynyl, —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)—C₄₋₆ heterocyclyl,—(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, —(CH₂)_(n)OR_(f),—S(O)_(p)R^(f), —C(═O)NR^(f)R_(f), —NR^(f)C(═O)R^(f),—S(O)_(p)NR^(f)R_(f), —NR^(f)S(O)_(p)R^(f), —NR^(f)C(═O)OR^(f),—OC(═O)NR^(f)R^(f) and —(CH₂)_(n)NR^(f)R_(f); R^(f), at each occurrence,is independently selected from H, F, Cl, Br, CN, OH, C₁₋₅alkyl(optionally substituted with halogen and OH), C₃₋₆ cycloalkyl, andphenyl; n, at each occurrence, is independently selected from zero, 1,2, 3, and 4; and p, at each occurrence, is independently selected fromzero, 1, and
 2. 3. The compound according to claim 2 having Formula(II):

or a stereoisomer, an enantiomer, a diastereoisomer, a tautomer, or apharmaceutically acceptable salt thereof, wherein: ring B isindependently selected from

R¹, at each occurrence, is independently selected from H, F, Cl, OH, CN,C₁₋₄ alkyl, OC₁₋₄ alkyl, and C₃₋₆ cycloalkyl; R² is independentlyselected from C₁₋₅ alkyl substituted with 0-3 R^(e); C₂₋₅ alkenyl, arylsubstituted with 0-3 R^(e), heteroaryl substituted with 0-3 R^(e), C₃₋₆cycloalkyl, —(CH₂)₁₋₄OC₁₋₅alkyl, and —(CH₂)₁₋₃OC₃₋₆cycloalkyl; R³ and R⁴together with the nitrogen atom to which they are both attached form aheterocyclic ring selected from

R⁵, at each occurrence, is independently selected from OH,—(CR⁷R⁷)_(n)—R⁶, —OR⁶, —S(O)_(p)R⁶, —C(═O)R⁶, —NR^(a)R⁶, —C(═O)NR^(a)R⁶,—NR^(a)C(═O)R⁶, —NR^(a)C(═O)OR⁶, —OC(═O)NR^(a)R⁶, —C(═O)OR⁶,—S(O)_(p)NR^(a)R⁶, —NR^(a)S(O)_(p)NR^(a)R⁶, and —NR^(a)S(O)_(p)R⁶;R^(5a) is independently selected from —C(═O)OR⁶, —C(═O)NR^(a)R⁶,—(CR⁷R⁷)_(n)—R⁶, —C(═O)—R⁶, and —S(O)_(p)R⁶; R⁶, at each occurrence, isindependently selected from —(CR⁷R⁷)_(n)-aryl, —(CR⁷R⁷)_(n)—C₃₋₆cycloalkyl, and —(CR⁷R⁷)_(n)-heteroaryl, each substituted with 0-3 R⁸;R⁷, at each occurrence, is independently selected from H, C₁₋₄ alkyl,and (CH₂)_(n)—C₃₋₁₂ carbocyclyl substituted with 0-3 R^(e); R⁸, at eachoccurrence, is independently selected from H, F, Cl, Br, —OR^(b),—(CH₂)_(n)C(═O)R^(b), —(CH₂)_(n)C(═O)OR^(b), —(CH₂)_(n)NR^(a)R^(a), CN,—(CH₂)_(n)C(═O)NR^(a)R^(a), C₁₋₄ alkyl substituted with 0-3 R^(e),—(CH₂)_(n)—C₃₋₆ carbocyclyl substituted with 0-3 R^(e), and—(CH₂)_(n)-heterocyclyl substituted with 0-3 R^(e); R^(a), at eachoccurrence, is independently selected from H, C₁₋₆ alkyl substitutedwith 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e),and —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e); or R^(a) andR^(a) together with the nitrogen atom to which they are both attachedform a heterocyclic ring substituted with 0-5 R^(e); R^(b), at eachoccurrence, is independently selected from H, C₁₋₆ alkyl substitutedwith 0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5 R^(e), C₂₋₆ alkynylsubstituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e);R^(e), at each occurrence, is independently selected from F, Cl, Br, CN,NO₂, ═O, CO₂H, C₁₋₆ alkyl (optionally substituted with F and Cl), OH,OCH₃, OCF₃, —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)—C₄₋₆ heterocyclyl,—(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, and —(CH₂)_(n)OC₁₋₄ alkyl; andn, at each occurrence, is independently selected from zero, 1, 2, 3, and4.
 4. A compound according to claim 3, or a stereoisomer, an enantiomer,a diastereoisomer, a tautomer, or a pharmaceutically acceptable saltthereof, wherein: R¹, at each occurrence, is independently selected fromH, F, Cl, OH, CN, C₁₋₄ alkyl, and OC₁₋₄ alkyl; R² is independentlyselected from C₁₋₅ alkyl substituted with 0-3 R^(e); C₂₋₅ alkenyl,phenyl substituted with 0-3 R^(e), 5- to 6-membered heteroarylsubstituted with 0-3 R^(e), C₃₋₆ cycloalkyl, and CH₂O(CH₂)₁₋₃CH₃; R³ andR⁴ together with the nitrogen atom to which they are both attached forma heterocyclic ring selected from

R⁵ is independently at each occurrence, selected from OH,

R⁸, at each occurrence, is independently selected from H, F, Cl, Br,—OCH₃, —OCF₃, ═O, CN, CH₃, CF₃—(CH₂)_(n)-aryl, —(CH₂)_(n)—C₃₋₆cycloalkyl substituted with 0-3 R^(e), and —(CH₂)_(n)-heterocyclylsubstituted with 0-3 R^(e); R^(8a), at each occurrence, is independentlyselected from H, CH₃, aryl substituted with 0-3 R^(e), and heterocyclylsubstituted with 0-3 R^(e); R^(a), at each occurrence, is independentlyselected from H, C₁₋₆ alkyl substituted with 0-5 R^(e),—(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e), and—(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e); R^(e), at eachoccurrence, is independently selected from F, Cl, Br, CN, NO₂, ═O, CO₂H,C₁₋₆ alkyl (optionally substituted with F and Cl), OH, OCH₃, OCF₃,—(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)—C₄₋₆ heterocyclyl,—(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, and —(CH₂)_(n)OC₁₋₄alkyl; and n,at each occurrence, is independently selected from zero, 1, 2, and
 3. 5.A compound according to claim 4, having Formula (III):

or a stereoisomer, an enantiomer, a diastereoisomer, a tautomer, or apharmaceutically acceptable salt thereof, wherein: ring B isindependently selected from

R¹, at each occurrence, is independently selected from H, F, Cl, OH, CN,C₁₋₄ alkyl, and OC₁₋₄ alkyl; R² is independently selected from C₁₋₅alkyl substituted with 0-3 R^(e); C₂₋₅ alkenyl, phenyl substituted with0-3 R^(e), 5- to 6-membered heteroaryl substituted with 0-3 R^(e), C₃₋₆cycloalkyl, and CH₂O(CH₂)₁₋₃CH₃; R⁵ is independently at each occurrence,selected from OH,

R⁸, at each occurrence, is independently selected from H, F, Cl, Br,—OCH₃, —OCF₃, ═O, CN, CH₃, CF₃, —C(═O)NH₂, —(CH₂)_(n)-aryl substitutedwith 0-3 R^(e), —(CH₂)_(n)—C₃₋₆ cycloalkyl substituted with 0-3 R^(e),and —(CH₂)_(n)-heterocyclyl substituted with 0-3 R^(e); R^(8a), at eachoccurrence, is independently selected from H, CH₃, aryl substituted with0-3 R^(e), and heterocyclyl substituted with 0-3 R^(e); R^(a), at eachoccurrence, is independently selected from H, C₁₋₆ alkyl substitutedwith 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e),and —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e); R^(e), at eachoccurrence, is independently selected from F, Cl, Br, CN, NO₂, ═O, CO₂H,C₁₋₆ alkyl (optionally substituted with F and Cl), —OH, —OCH₃, —OCF₃,—(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)—C₄₋₆ heterocyclyl,—(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, and —(CH₂)_(n)OC₁₋₄alkyl; and n,at each occurrence, is independently selected from zero, 1, 2, and
 3. 6.A compound according to claim 3, or a stereoisomer, an enantiomer, adiastereoisomer, a tautomer, or a pharmaceutically acceptable saltthereof, wherein: R¹, at each occurrence, is independently selected fromF, Cl, —OH, —CH₂CH₃, —OCH₃, and —OCD₃; R² is independently selected fromC₁₋₅ alkyl substituted with 0-3 R^(e); C₂₋₅ alkenyl, phenyl substitutedwith 0-3 R^(e), 5- to 6-membered heteroaryl substituted with 0-3 R^(e),C₃₋₆ cycloalkyl, and —CH₂O(CH₂)₁₋₃CH₃; R³ and R⁴ together with thenitrogen atom to which they are both attached form

R⁵, at each occurrence, is independently at each occurrence, selectedfrom —OH, F, and C₁; R^(5a), at each occurrence, is independentlyselected from

R⁸, at each occurrence, is independently selected from H, F, Cl, Br,—OCH₃, —O(CH₂)₁₋₃OCH₃, —OCF₃, ═O, CN, CH₃, CF₃—(CH₂)_(n)-aryl,—(CH₂)_(n)—C₃₋₆ cycloalkyl substituted with 0-3 R^(e), and—(CH₂)_(n)-heterocyclyl substituted with 0-3 R^(e); R^(8a), at eachoccurrence, is independently selected from H, CH₃, aryl substituted with0-3 R^(e), and heterocyclyl substituted with 0-3 R^(e); R^(a), at eachoccurrence, is independently selected from H, C₁₋₆ alkyl substitutedwith 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e),and —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e); R^(b), at eachoccurrence, is independently selected from H, C₁₋₆ alkyl substitutedwith 0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5 R^(e), C₂₋₆ alkynylsubstituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e);R^(e), at each occurrence, is independently selected from F, Cl, Br, CN,NO₂, ═O, CO₂H, C₁₋₆ alkyl (optionally substituted with F and Cl), OH,OCH₃, OCF₃, —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)—C₄₋₆ heterocyclyl,—(CH₂)_(n)-aryl, and —(CH₂)_(n)-heteroaryl; and n, at each occurrence,is independently selected from zero, 1, 2, and
 3. 7. A compoundaccording to claim 1, or a stereoisomer, an enantiomer, adiastereoisomer, a tautomer, or a pharmaceutically acceptable saltthereof, wherein: R¹, at each occurrence, is independently selected from—CH₂OH, —OCH₃, —OCH₃, —OCF₃, OCH₂Ph, —C(═O)NR^(a)R^(a), —NR^(a)R^(a),CH₃, CH₂CH₃, CH(CH₃)₂, and cyclopropyl; R² is independently selectedfrom C₁₋₄ alkyl substituted with 0-3 R^(e); C₂₋₄ alkenyl, phenylsubstituted with 0-3 R^(e), 5- to 6-membered heteroaryl substituted with0-3 R^(e), C₃₋₆ cycloalkyl, and CH₂O(CH₂)₁₋₃CH₃; R³ is independentlyselected from H and C₁₋₄ alkyl: R⁴ is independently selected from—(CHR⁷)₁₋₄—R⁶, —(CH₂)₁₋₃OR⁶, —(CH₂)₁₋₃NHR⁶, and —(CH₂)₀₋₃NHC(═O)R⁶; R⁶,at each occurrence, is independently selected from —(CR⁷R⁷)_(n)-aryl,—(CR⁷R⁷)_(n)—C₃₋₆ cycloalkyl, and —(CR⁷R⁷)_(n)-heteroaryl, eachsubstituted with 0-3 R⁸; R⁷, at each occurrence, is independentlyselected from H, C₁₋₄ alkyl, and aryl; R⁸, at each occurrence, isindependently selected from H, F, Cl, —OR^(b), —NR^(a)R^(a), C₁₋₄ alkylsubstituted with 0-3 R^(e), phenyl substituted with 0-3 R^(e), andheterocyclyl substituted with 0-3 R^(e); R^(a), at each occurrence, isindependently selected from H, C₁₋₆ alkyl substituted with 0-5 R^(e),—(CH₂)_(n)-phenyl substituted with 0-5 R^(e), and —(CH₂)_(n)-heteroarylsubstituted with 0-5 R^(e); R^(b), at each occurrence, is independentlyselected from H, C₁₋₆ alkyl substituted with 0-5 R^(e),—(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e), and—(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e); R^(e), at eachoccurrence, is independently selected from F, Cl, Br, CN, NO₂, ═O, CO₂H,C₁₋₆ alkyl (optionally substituted with F and Cl), OH, OCH₃, OCF₃,—(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)—C₄₋₆ heterocyclyl,—(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl; and n is independently selectedfrom zero, 1, 2, 3, and
 4. 8. A compound according to claim 5, havingFormula (IV):

or a stereoisomer, an enantiomer, a diastereoisomer, a tautomer, or apharmaceutically acceptable salt thereof, wherein: R¹, at eachoccurrence, is independently selected from F, Cl, OH, C₁₋₄ alkyl, andOC₁₋₄ alkyl; R² is independently selected from —CH₂CH₂CH₂CH₃,—CH₂CH₂CH(CH₃)₂, CH₂CH₂CH₂CF₃, —CH₂-cyclopropyl, —CH₂CH₂-cyclopropyl,cyclobutyl, cyclopentyl, —CH₂O(CH₂)₁₋₃CH₃, —CH₂OCH(CH₃)₂, phenylsubstituted with 0-2 R^(e), and 5- to 6-membered heteroaryl substitutedwith 0-2 R^(e); R⁵, at each occurrence, is independently selected from

R⁸, at each occurrence, is independently selected from F, Cl, Br, —OCH₃,—OCF₃, ═O, CN, CH₃, CF₃, —C(═O)NH₂, —(CH₂)_(n)-aryl substituted with 0-3R^(e), —(CH₂)_(n)—C₃₋₆ cycloalkyl substituted with 0-3 R^(e), and—(CH₂)_(n)-heterocyclyl substituted with 0-3 R^(e); R^(e), at eachoccurrence, is independently selected from F, Cl, Br, CN, NO₂, ═O, CO₂H,C₁₋₆ alkyl (optionally substituted with F and Cl), OH, OCH₃, OCF₃,—(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)—C₄₋₆ heterocyclyl,—(CH₂)_(n)-aryl, and —(CH₂)_(n)-heteroaryl; and n is independentlyselected from zero, 1, 2, 3, and
 4. 9. A compound according to claim 8,or a stereoisomer, an enantiomer, a diastereoisomer, a tautomer, or apharmaceutically acceptable salt thereof, wherein: R¹ is both CH₂CH₃ orboth OCH₃; R² is independently selected from

R⁵ is independently at each occurrence, selected from

R⁸, at each occurrence, is independently selected from F, Cl, Br, —OCH₃,—OCF₃, CN, CH₃, and CF₃; and R^(e), at each occurrence, is independentlyselected from F, Cl, Br, C₁₋₃ alkyl, and cyclopropyl.
 10. A compoundaccording to claim 5, having Formula (V):

or a stereoisomer, an enantiomer, a diastereoisomer, a tautomer, or apharmaceutically acceptable salt thereof, wherein: ring B isindependently selected from

R¹, at each occurrence, is independently selected from H, F, Cl, OH, CN,and OC₁₋₄ alkyl; R² is independently selected from —CH₂CH₂CH₂CH₃,—CH₂CH₂CH(CH₃)₂, CH₂CH₂CH₂CF₃, —CH₂-cyclopropyl, —CH₂CH₂-cyclopropyl,cyclobutyl, cyclopentyl, CH₂O(CH₂)₁₋₃CH₃, and CH₂OCH(CH₃)₂, phenylsubstituted with 0-2 R^(e), and 5- to 6-membered heteroaryl substitutedwith 0-2 R^(e); R⁵, at each occurrence, is independently selected from

R⁸, at each occurrence, is independently selected from F, Cl, Br, —OCH₃,—OCF₃, ═O, CN, CH₃, CF₃, —C(═O)NH₂, —(CH₂)_(n)-aryl substituted with 0-3R^(e), —(CH₂)_(n)—C₃₋₆ cycloalkyl substituted with 0-3 R^(e), and—(CH₂)_(n)-heterocyclyl substituted with 0-3 R^(e); R^(e), at eachoccurrence, is independently selected from F, Cl, Br, CN, NO₂, ═O, CO₂H,C₁₋₆ alkyl (optionally substituted with F and Cl), OH, OCH₃, OCF₃,—(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)—C₄₋₆ heterocyclyl,—(CH₂)_(n)-aryl, and —(CH₂)_(n)-heteroaryl; R^(e′) is independentlyselected from C₁₋₂ alkyl, —CH₂OC₁₋₂ alkyl, and cyclopropyl; and n isindependently selected from zero, 1, 2, 3, and
 4. 11. A compoundaccording to claim 10, having Formula (VI):

or a stereoisomer, an enantiomer, a diastereoisomer, a tautomer, or apharmaceutically acceptable salt thereof, wherein: R¹, at eachoccurrence, is independently selected from H, F, Cl, OH, CN, and OC₁₋₄alkyl; R² is independently selected from —CH₂CH₂CH₂CH₃, —CH₂CH₂CH(CH₃)₂,CH₂CH₂CH₂CF₃, —CH₂-cyclopropyl, —CH₂CH₂-cyclopropyl, cyclobutyl,cyclopentyl, CH₂O(CH₂)₁₋₃CH₃, and CH₂OCH(CH₃)₂,

R⁵, at each occurrence, is independently selected from

R⁸, at each occurrence, is independently selected from F, Cl, Br, —OCH₃,—OCF₃, ═O, CN, CH₃, CF₃, —C(═O)NH₂, —(CH₂)_(n)-aryl substituted with 0-3R^(e), —(CH₂)_(n)—C₃₋₆ cycloalkyl substituted with 0-3 R^(e), and—(CH₂)_(n)-heterocyclyl substituted with 0-3 R^(e); R^(e), at eachoccurrence, is independently selected from F, Cl, Br, CN, NO₂, ═O,—CO₂H, C₁₋₆ alkyl (optionally substituted with F and Cl), —OH, —OCH₃,—OCF₃, —(CH₂)_(n)—C₃-6 cycloalkyl, —(CH₂)_(n)—C₄₋₆ heterocyclyl,—(CH₂)_(n)-aryl, and —(CH₂)_(n)-heteroaryl; R^(e′) is independentlyselected from C₁₋₂ alkyl, —CH₂OC₁₋₂ alkyl, and cyclopropyl; and n isindependently selected from zero, 1, 2, 3, and
 4. 12. A compoundaccording to claim 3, having Formula (VII):

or a stereoisomer, an enantiomer, a diastereoisomer, a tautomer, or apharmaceutically acceptable salt thereof, wherein: R¹, at eachoccurrence, is independently selected from F, Cl, —OH, C₁₋₂ alkyl, and—OC₁₋₂ alkyl; R² is independently selected from —CH₂CH₂CH₂CH₃,—CH₂CH₂CH(CH₃)₂, —CH₂CH₂CH₂CF₃, —CH₂-cyclopropyl, —CH₂CH₂-cyclopropyl,cyclobutyl, cyclopentyl, —CH₂O(CH₂)₁₋₃CH₃, —CH₂OCH(CH₃)₂, phenylsubstituted with 0-2 R^(e), and 5- to 6-membered heteroaryl substitutedwith 0-2 R^(e); R³ and R⁴ together with the nitrogen atom to which theyare both attached form a heterocyclic ring selected from

R⁵ is independently at each occurrence, selected from

R⁸, at each occurrence, is independently selected from F, Cl, Br, —OCH₃,—OCF₃, CN, CH₃, CF₃, —C(═O)NH₂, —(CH₂)_(n)-aryl substituted with 0-3R^(e), —(CH₂)_(n)—C₃₋₆ cycloalkyl substituted with 0-3 R^(e), and—(CH₂)_(n)-heterocyclyl substituted with 0-3 R^(e); R^(e), at eachoccurrence, is independently selected from F, Cl, Br, CN, NO₂, ═O, CO₂H,C₁₋₆ alkyl (optionally substituted with F and Cl), —OH, —OCH₃, —OCF₃,—(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)—C₄₋₆ heterocyclyl,—(CH₂)_(n)-aryl, and —(CH₂)_(n)-heteroaryl; and n is independentlyselected from zero, 1, 2, 3, and
 4. 13. A compound according to claim 1,wherein the compound is selected from the exemplified examples or astereoisomer, an enantiomer, a diastereoisomer, a tautomer, or apharmaceutically acceptable salt thereof.
 14. A pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and acompound of claim 1, or a stereoisomer, a tautomer, or apharmaceutically acceptable salt thereof.
 15. A method of treatingcardiovascular diseases, comprising administering to a patient in needthereof a therapeutically effective amount of the pharmaceuticalcomposition of claim
 14. 16. The method of claim 15 wherein saidcardiovascular diseases are coronary heart disease, stroke, heartfailure, systolic heart failure, diastolic heart failure, diabetic heartfailure, heart failure with preserved ejection fraction, cardiomyopathy,myocardial infarction, left ventricular dysfunction, left ventriculardysfunction after myocardial infarction, cardiac hypertrophy, myocardialremodeling, myocardial remodeling after infarction or after cardiacsurgery and valvular heart diseases.